Nanoparticle-based photo-triggered cancer immunotherapy and its

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Nanoparticle-based photo-triggered cancer immunotherapy and its domino effect in the tumor microenvironment Santhosh Kalash Rajendrakumar, Saji Uthaman, Chong Su Cho, and In-Kyu Park Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.8b00460 • Publication Date (Web): 20 Apr 2018 Downloaded from http://pubs.acs.org on April 20, 2018

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Nanoparticle-based photo-triggered cancer immunotherapy and its domino effect in the tumor microenvironment

Santhosh Kalash Rajendrakumar§, Saji Uthaman‡, Chong-Su Cho†*, and In-Kyu Park§*

§Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju 61469, South Korea. E-mail: [email protected] ‡Department of Polymer Science and Engineering, Chungnam National University, 99 Daehakro, Yuseong-gu, Daejeon, 34134, South Korea. †Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 08826, South Korea. E-mail: [email protected]

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ABSTRACT Immune system evasion by cancer cells is one of the hallmarks of cancers, and it occurs with the support of tumor-associated immune cells (TICs) in the tumor microenvironment that increase the growth and invasiveness of tumor cells. With recent advancements in the development of novel near infrared (NIR)-responsive nanoparticles, specifically eradicating TICs or inducing an inflammatory immune response by activating killer T cells has become possible. This review will discuss the mechanisms and applications of photo-triggered immunotherapy in detail. In addition, various nanoparticles employed in photo-triggered immunotherapy for cancer treatment will be covered. Furthermore, the challenges and future directions of photo-triggered nanoparticle development for anticancer immunotherapy will be briefly discussed.

KEYWORDS: Photoimmunotherapy, Photothermal therapy, Photodynamic therapy, Immune cells, Nanoparticle, Near-infrared


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INTRODUCTION Over the past few decades, the rapid development of therapeutic drugs for cancer treatment has focused on preventing tumor recurrence in the physiological system. During these attempts, many interventional therapies, such as microRNA, siRNA, and antibody therapies and inhibitor treatments, have emerged, resulting in the enhancement of drug treatment effectiveness.1-6 Currently, the administration of chemo-drugs along with pre-activated immune cells are being employed as a new treatment strategy in clinical trials for castration-resistant cancer patients.7-9 However, the therapeutic outcomes, such as apoptosis, anticancer immune response activation, anti-metastasis, and tumor-associated immune cell reduction, basically depend on the active therapeutic dosage that accumulates in the tumor.10, 11 Hence, improving the targeting efficacy and overcoming the tumor-associated immune cell barrier are challenging tasks to accomplish.12, 13

Other challenges with the systemic administration of chemo-immune drugs include loss of

efficacy, variable antigen expression, the tumor microenvironment, and poor immune activation in malignancy patients.14 Recent advances in nano-based materials, such as metal-, polymer-, carbon-, and lipid-based nanoparticles, have shown a unique opportunity to safely and efficiently deliver single or multiple chemo-immune drugs to tumor sites.13,

15-18

Nanoparticle systems prevent systemic

toxicity and enhance the distribution of chemo-immune drugs to tumors. In addition, along with systemic therapy, external treatments, such as hyperthermia, photothermal (PTT), photodynamic (PDT), or high-intensity focused ultrasound (HIFU) therapies, could be employed to cause extensive tumor killing with minimal accumulation of active therapeutic drugs in the tumor 3 ACS Paragon Plus Environment


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(Figure 1).19-22 However, external therapeutic intervention along with chemotherapy has been shown to have limited effects on tumor suppression due to other mechanisms such as cancer immune escape, abnormal immune activation by the nanomaterials, and tumor growth promotion by anti-inflammatory cytokines.

Figure 1: Schematic representation of preclinical combinatorial treatment strategies with external and systemic therapy. External therapy involves photothermal therapy (PTT), photodynamic therapy (PDT), high-intensity-focused ultrasound (HIFU) therapy, and radiotherapy, whereas systemic treatments include chemotherapy and immunotherapy.21, 23-29 4 ACS Paragon Plus Environment

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A combinatorial treatment regimen with external and systemic therapies can have positive effects on metastasis, treatment toxicity, and tumor recurrence.30, 31 Tumor-focused treatments, such as photothermal, photodynamic and HIFU therapies, can lead to tumor regression and can prevent cytotoxicity in healthy tissues.28, 32, 33 Laser-mediated tumor ablation is preferred over HIFU treatment because complete tumor growth retardation occurs with single time irradiation in laser treatment, whereas the HIFU treatment causes only necrosis in the superficial region of tumor.22, 34, 35 Alternatively, phototherapy can be an effective treatment strategy in conjunction with systemic therapies. Recently, Liu et al. developed a tantalum sulfide (TaS2) nanosheet loaded with doxorubicin for chemo-photothermal therapy.36 Doxorubicin-loaded lipid PEGstabilized TaS2-treated PC3 xenograft tumor mice irradiated with an 808-nm laser showed complete reduction in their tumor volumes without causing side effects in other organs.36 The combined effect of targeted phototherapy and chemotherapy can eradicate solid tumors efficiently with few side effects.37-39 However, this combinatorial treatment has been less efficacious with aggressive and malignant cancers due to the reason that enormous cancer associated immune cells in the tumor microenvironment, such as tumor-associated macrophages (TAMs), tumor-associated dendritic cells (TADs), and myeloid-derived suppressor cells (MDSCs), inhibit anti-tumor immune response and support the recurrence of malignant tumor cells.40-43 During phototherapy, tumor antigen released from the ablated tumor region is recognized and presented by the antigen-presenting cells in tumor-draining lymph nodes (TDLNs) to T lymphocytes, causing an anticancer immune response against specific cancer cells.44 Additionally, to improve the function of immune cells and to overcome immune suppressive blockers, adjuvants are required for an anticancer immune response.45, 46 5 ACS Paragon Plus Environment


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Therefore, a combination of phototherapy and immunotherapy can facilitate the enhancement of an antitumor immune response as well as the activation and proliferation of memory immune cells such as CD45RO+ T cells.47 Hence, the relationship between phototherapy and immunotherapy must be clearly understood to develop efficient cancer treatment strategies. In the current review, the mechanism and limitations of nanoparticle-based photo-therapies, such as photothermal and photodynamic therapies, as well as the mechanism and future aspects of nanoparticle-based combined cancer phototherapy and immunotherapy, will be discussed in detail.

PHOTOTHERAPY: MECHANISM AND APPLICATION IN CANCER Hyperthermia treatment is a currently progressing treatment strategy that has been determined to improve the therapeutic outcome of cancer.48 In hyperthermia treatment for cancer, after injecting a patient with therapeutic agents, such as near-infrared (NIR) dyes, metallic nanoparticles or carbon nanoparticles, the tumor site is irradiated using either a laser or an alternating magnetic field (AMF) as the external source.49 Above 49°C, the tumor cell proteins lose structural and functional properties that lead to the induction of programmed cell death.50 Along with hyperthermia, several strategies have been developed to co-deliver drugs or therapeutic interventions to enhance this cell death.51 One limitation of hyperthermia using an AMF is achieving a temperature >49°C in a tumor, as the temperature that can be achieved is relatively proportional to the tumor concentration of magnetic agents such as

(SPIONs).52

Alternatively, NIR-based phototherapy provides proper tumor depth penetration, elevated temperature, and tumor-specific ablation.53 NIR-based phototherapy includes photothermal therapy and photodynamic therapy, where their therapeutic efficacies depend on several factors 6 ACS Paragon Plus Environment

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such as the used laser power density, tumor ablation agents (i.e., temperature or ROS), and quantum yield; PDT is also affected by the tumor oxygen level (Figure 2).54-57 Furthermore, the utilization of biodegradable and non-toxic cancer targeting nanoparticles which carry PDT or PTT agents to tumor can enhance the laser mediated tumor ablation.58 The key component in photothermal therapy is the lesion temperature, which has to be monitored carefully because a high temperature will transfer heat to healthy tissues, killing them along with the tumor.59 Consequently, the use of a multimodal-imaging system along with photothermal treatment could avoid healthy tissue damage and focus heat on cancerous cells alone. Nanoparticles, such as the Mn-doped Fe3O4@MoS2 nanoflowers developed by Xunan Jing et al., exhibit NIR photothermal heat conversion as well as T1/T2 MRI contrast.60 NIR-based photothermal therapy also requires a highly focused NIR laser and a PTT agent with NIR photothermal heat conversion properties.61 When employing an NIR laser for PTT, the critical factor is optimizing the laser power density since sudden increases in the temperature above 45°C will injure normal tissue (Figure 2a).62, 63 Hence, Zhu et al. assessed the effect of PTT in a phantom tube with double-layered cancer cells and normal cells via irradiation using a 730-nm laser at 0.3-0.8 W/cm2.64 In this system, laser irradiation with the power intensity of 0.8 W/cm2 showed an increase in temperature above 45°C in the cancer cell layer even though the temperature of the normal cell layer was 2°C less, indicating that heat transfer to the normal cells occurred at the level below the protein denaturation temperature.64 In addition, the use of metalbased scaffold implantation and upconversion nanocomposites can prevent thermal transfer to the normal tissue region and can enhance photothermal ablation to the tumor tissue alone.64, 65 Targeting tumor cells alone using targeting ligands, such as antibodies, peptides or small molecules conjugated to a PTT agent, is highly feasible and could avoid side effects while 7 ACS Paragon Plus Environment


effectively destroying a tumor via laser-mediated ablation.66,

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67

The deciding factors for

optimized power density are the quantum yield and the concentration of the PTT agent accumulated in the tumor (Figure 2a).68, 69 To enhance the photothermal-based anticancer effect, PTT can be accompanied by chemodrugs for synergistic reduction of the tumor volume, therefore reducing the chances of tumor recurrence.70-72 In addition, photothermal-assisted chemotherapy can significantly reduce the IC50 value of a drug compared to traditional chemotherapy.73 Recently, Jun Jin et al. developed a photochemotherapy-based nanoparticle using graphdiyne nanosheets loaded with DOX by Π-Π stacking, and it significantly eradicated an MDA-MB-231 breast cancer tumor upon NIR laser irradiation.74

Figure 2: Critical factors required for effective tumor ablation in photothermal and photodynamic therapies. Schematic representation of a) factors responsible for efficient photothermal therapy are laser power density (watt/cm2), temperature rise (∆T), quantum yield [(Φ(λ)], (b) factors responsible for efficient photodynamic therapy are laser power density (joules/cm2), ROS generation (•O−2, •OH, H2O2), and oxygen supply (mm Hg) and c) cancer


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specific and biodegradable nanoparticles to deliver PDT or PTT agents efficiently for tumor ablation. 54-57, 75

PTT agents must be biodegraded in the physiological system and excreted in a non-toxic form (Figure 2c).57 Shao et al. studied the degradation of PLGA nanoparticles loaded with black phosphorous quantum dots (BPQDs) in the physiological environment for 8 weeks. The BPQDs were observed to degrade into nontoxic phosphate and phosphonate, whereas the PLGA nanoparticles degraded completely into CO2 and H2O molecules within 8 weeks.76 Carbon based PDT/PTT agents undergoes enzymatic degradation by immune cells. Hyunwoo Kim et al., has shown that graphene oxide easily be degraded by peroxidase enzymes in the macrophage.77 Similarly, metal based PTT agents like gold nanoparticle has been shown to be biodegradable and has fast blood clearance depending on their size and surface chemistry.78, 79 Especially, NIR gold nanorods experienced reshaping into spherical particles after laser irradiation, which prevented unwanted cell damage following the destruction of target cells and also allowed for fast clearance of the remaining spherical gold particle from the blood stream.80 Along with biodegradation, nanoparticles targeting cancer specifically could enhance the photothermal mediated killing in cancer stem cells (CSC) that supports in cancer metastasis. Hai Wang et al., developed a hyaluronic acid-decorated fullerene-silica PTT/PDT/chemo-based nanoparticle for targeting and eliminating cancer stem-like cells by photothermal ablation.81 Cancer stem-like cells are CD44 receptor over expressing cells that supports tumor in metastasis and immune evasion.82, 83 Therefore, targeting CD44 receptor could specifically enhance the killing of cancer stem cells and prevent tumor recurrence after NIR irradiation. Apart from these, the nanoparticle should also be designed in such a way that it can penetrate into deep tumor tissues and 9 ACS Paragon Plus Environment


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distributed evenly over the tumors for enhanced PDT or PTT effect.84, 85 Wang et al., developed a iRGD conjugated lipid based nanoparticle for the delivery of ICG and tirapazamine (TPZ), a hypoxia-activated anti-cancer prodrug (iNP/IT) for combinatorial photo-hypoxia activated prodrug therapy.86 The even distribution of iNP/IT nanoparticle in the deep tumor has led to activation of TPZ due to hypoxic condition and therefore upon laser irradiation, synergistic effect of activated TPZ and ICG mediated tumor ablation has led to complete tumor destruction. 86

Overall, in order to overcome the increased interstitial fluid pressure and the dense tumor

stroma barrier, it has been necessary to develop nanoparticle conjugated with tissue penetrating peptides or ligands for enhanced tumor killing by PTT or PDT. Overall, the laser power density, quantum yield, and generated thermal heat are important factors for efficient photothermal therapy in cancer. Intracellular molecular oxygen are also considered as one of the key components required for a profound PDT effect in solid tumors (Figure 2b).75 The major factor that diminishes the effectiveness of PDT in solid tumors is a hypoxic condition created in tumor microenvironment during tumor growth, where the supply of oxygen is drastically reduced due to the uncontrolled proliferation and expansion of cancer cells.87 Hypoxia also occurs after PDT because it consumes oxygen and destroys the tumor vasculature.88 Reed et al. explained that after PDT, the tumor partial oxygen pressure (PO2) was drastically reduced with increasing time, the major cause of which was decreased blood flow that lead to hypoxia in a subcutaneous chondrosarcoma.87 One of the solutions to this problem could be hyper-oxygenating the tumor during PDT treatment;89 catalyzing the endogenous hydrogen peroxide (H2O2) to produce oxygen are also currently been studied for the enhancement of PDTmediated tumor killing.90 Zhang et al. used PEGylated Pt-decorated porphyrinic metal-organic framework (MOF) PCN-224 nanoconjugates to convert H2O2 to O2, and after irradiation with a 10 ACS Paragon Plus Environment

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660-nm laser, the effect of PDT was improved in the hypoxic sites of H22 tumors in mice.91 Enhanced amount of O2 generated by PCN-224-Pt improved the PDT efficiency inside the hypoxic tumor environment in the presence of H2O2. For deep tissue tumors, NIR laser with wavelength at 660 or 780 were not sufficient for causing PDT due to lose of light propagation and poor interaction between dye molecules and laser in the deep tissues.92 Hence, macroscopic tumors and metastases are also not easily treatable by PDT.93 Several strategies using Förster resonance energy transfer (FRET) – and Bioluminescence resonance energy transfer (BRET)-based nanoparticles could overcome poor deep tissue penetration. FRET-based nanoparticles, such as upconversion nanoparticles, could transfer NIR light energy to visible light energy, which could then irradiate photosensitizers.94 BRET-based nanoparticles utilize bioluminescence energy to excite photosensitizers, resulting in the production of ROS in tumor tissues.93, 95 Another factor that hinders the application of PDT in cancer is the significant toxicity induced by PDT lasers in surrounding tissue.96, 97 Zhu et al. developed nanoceria-doped semiconducting polymeric nanoparticles that acted as ROS scavengers in neutral tissue pH (7.4) after 660-nm laser irradiation but, in the acidic tumor environment, produced free radicals.98 These nanoparticles reduced non-specific damage to healthy tissues and induced cell apoptosis only in the cancer cells. Most other PDT studies have been performed using dye-based photosensitizers loaded inside nanoparticles such as liposomes or micelles; however, these systems have leakage problems that must be addressed for efficient cargo delivery because leaked dye photosensitizers could be toxic to healthy tissues after laser irradiation. Recently, Xu et al. developed upconversion nanoparticles that were co-loaded in mesoporous silica nanoparticles with green light- and red light-excited photosensitizers such as the chlorin e6 and MC540 dyes.99 The 11 ACS Paragon Plus Environment


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compactness of the mesoporous silica nanoparticles and the usage of NIR light upconversion nanoparticles prevented systemic toxicity of the photosensitizers in a mouse uterine cervical carcinoma tumor model.99 Dual therapies have advantages over singular therapies in terms of improving the therapeutic efficacy and obtaining the best treatment outcome.100 To achieve a high therapeutic index, combined phototherapies can be used since they show outstanding synergism and can compensate for the limitations of single therapies.101 The treatment based on dual therapies of PDT and PTT was shown to enhance the killing of tumors with lower doses of laser irradiation.102-106 Kalluru et al. showed that folate-conjugated PEGylated graphene oxide (GOPEG-folate) generated free radicals (1O2) and promoted the photothermal therapeutic destruction of cancer cells in tumors.107 In this study, the tumor recurrence occurred only in 808-nm laser irradiation of FA-PEG-GO internalized tumors, whereas complete tumor growth retardation and skin healing occurred at the tumor sites accumulated with FA-PEG-GO after 980-nm laser irradiation.107 The complete tumor growth retardation could be due to the generation of both singlet oxygen and photothermal heat in the tumor after short-time irradiation using a 980-nm laser of GO-PEG-folate, whereas 808 nm laser irradiation produced only photothermal heat.107

TUMOR ASSOCIATED IMMUNE CELLS AND THEIR ROLE IN PHOTO-TRIGGERED CANCER THERAPY Before understanding the role of immune cells in photo-triggered cancer therapy, understanding the characteristic features of the immune system in the tumor microenvironment is necessary. In the tumor microenvironment, cells such as fibroblasts, myofibroblasts, neuroendocrine cells, and adipose cells support the tumorigenesis process, and immune cells, 12 ACS Paragon Plus Environment

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such as TAMs, TADs, regulatory T cells (Treg), and MDSCs, adhere to these cells during the initiation, progression and invasion of cancer cells.108 The major immune players that promote cancer progression are TAMs, and MDSCs, both of which accumulate and nourish tumors with their immune suppressive cytokines and chemokines such as interleukins (IL-10 and IL-8), transforming growth factor beta (TGF-β), and chemokine (C-C motif) ligands (CCL), including CCL17, CCL22, CCL24, CCL1 etc.109 MDSCs cells (CD11b+Ly-6G/C+) are generated from hematopoietic progenitor cells in bone marrow, and due to their recruitment in the tumor microenvironment, it lost its ability to differentiate into granulocytes, dendritic cells (DCs), monocytes, and macrophages.110, 111 Figure 3 shows that after photothermal ablation, MDSCs accumulate in secondary tumor sites and therefore cause increased activation of Treg (CD4, forkhead box P3 (FOXP3)+) cells; they later increase tumor remission by elevating TAMs and TADs.112 These occurrences can be overcome by the T cell adoptive transfer method in which antigen-specific T cells are adoptively transferred to patients after PTT treatment; however, single administration of these antigen specific T cells could not elevate the anti-tumor immune response completely.112 Circulating Ly6C+ CCR2+

monocytes from bone marrow hematopoietic stem cells are

recruited to the tumor microenvironment and differentiated into TAMs in the presence of cytokines such as M-CSF, IL-4, IL-3, IL-10, TGF-β, PGE2, and VEGF.113 TAMs accumulates in tumors and support in growth and invasion by secreting TNFα, IFN-β, matrix remodeling proteins like matrix metalloproteinase (MMPs) and expressing immunosuppressive elements like PDL-1, CTLA4 etc.113-115 Due to migration and accumulation of TAMs specifically in the tumor region, TAMs cell membrane loaded nanoparticle are been used to deliver therapeutic agents safely and securely to tumor sites.105,116 Xuan et al. loaded macrophage cell membrane with gold 13 ACS Paragon Plus Environment


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nanoshell nanoparticles (MPCM-AuNSs) and injected them intravenously.117 The accumulation of MPCM-AuNS nanoparticle were higher in the tumor region and after laser irradiation, the tumor growth was completely retarded.117

Figure 3. Photothermal-mediated immune response following tumor ablation mediated by nanoparticle-based PTT. a) After NIR laser irradiation, 1) the ablated tumor releases antigens, 2) proinflammatory cytokines are released along with antigens from the ablated tumor, 3) cytokines 14 ACS Paragon Plus Environment

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and antigens helps in maturation of immature dendritic cells in the tumor-draining lymph node (TDLN), 4) Myeloid derived suppressor cells (MDSCs), CD8+ and CD4+ T cells infiltrate in the ablated tumor, 5) CD8+ T cells induced anti-tumor immune response. b) Tumor recurrence appears 6) after the MDSC infiltration in the tumor, 7) anti-inflammatory cytokines are released from MDSCs, 8) CD4+ FOXP3 Treg cells are activated by MDSCs and inhibits anti-tumor immune response, 9) anti-inflammatory cytokines and Treg cells activated by MDSCs inhibits dendritic cell maturation, and 10) overall action of MDSCs cause tumor remission.112, 118, 119

During the initial development of a tumor, pro-inflammatory cells, such as M1 polarized macrophages, secrete nitric oxide (NO) that in turn promotes HIF-1α secretion and causes tumor cell death.120 The dead cells then secrete immunosuppressive factors such as IL-10, TGF-β, or sphingosine-1-phosphate (S1P), which mediate the polarization of M1 into M2 macrophages (anti-inflammatory).121 M2 polarized macrophages are TAMs, which secrete small amounts of NO, an effective tumoricidal agent.120 Apoptotic cells from the tumor secretes chemo-attractants such as monocyte chemoattractant protein-1 (MCP-1) and Bombesin (BN), that will initiate the infiltration of monocytes in the tumor microenviroment.122-124 The infiltrated monocytes differentiate into TAMs that support the progression of tumor growth and invasion.

122-124

The

possibility of PDT-mediated cell death in tumors occurs via the same phenomena (Figure 4).



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Figure 4. Photodynamic-mediated immune response following tumor necrosis after nanoparticlebased PDT. a) PDT laser irradiation in photosensitizer accumulated tumor leads to 1) ROSmediated cell death, b) after ROS mediated cell death, 2) apoptotic or necrotic cells attracts scavenging cells like mast cells, neutrophils, and monocytes, 3) apoptotic cancer cells release factors like IL-10, TGF-β, sphingosine-1-phosphate (S1P), monocyte chemoattractant protein-1 (MCP-1) and bombesin (BN), 4) released factors attracts monocytes and convert them into M2 16 ACS Paragon Plus Environment

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macrophages or tumor-associated macrophages (TAMs), and c) TAMs accumulated in the tumor site, 6) releases immune suppressive proteins and cytokines to support the growth and invasion of the tumor. 122-129 Hence, PDT- or PTT-based cytotoxicity against both cancer cells and TAMs can prevent tumor progression and metastasis. Interestingly, the TAMs in the tumor microenvironment are known to entrap large-size particles, drugs, mannosylated nanoparticles and small molecules; therefore, the likelihood of photosensitizers accumulating in TAM cells for PDT- or PTT-based tumor ablation are immense.130

PHOTOIMMUNOTHERAPY- A LIGHT-TRIGGERED DOMINO EFFECT OF IMMUNE SYSTEM IN TUMOR MICROENVIRONMENT. PDT and PTT strategies help to generate tumor-associated antigens, which in turn stimulate the stream of immune cells responsible for anticancer immune responses.131-133 After laser treatment, tumor lesions produce a wide range of antigens that specifically activate circulating immune cells such as dendritic cells, causing them to respond against the specific ablated tumor.134-137 The tumor antigens are taken up by dendritic cells and later processed in the Golgi bodies for major histocompatibility complex II (MHC II) antigen presentation to helper T cells.138 The activated CD4+ Th cells in turn activate other cytotoxic cells such as cytotoxic T cells and natural killer cells by secreting IL-2 cytokine.139-141 Memory immune cells, such as effector memory T cells from activated CD4+ and CD8+ T cells, and dendritic cells serve as preventive factors against the remission and metastasis of cancer cells.139, 142 The first domino event was initiated soon after NIR laser-mediated tumor ablation, at which time tumor antigens, such as necrotic or apoptotic cell bodies, are released into the blood stream 17 ACS Paragon Plus Environment


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and secondly been taken up by the circulating immature dendritic cells, causing their maturation.134-137

However, the maturation of dendritic cells requires additional immune

stimulators, such as synthetic nucleic acids (e.g., CpG oligonucleotide), poly I:C, chemoadjuvants (e.g., R848 and R837) and proinflammatory cytokines (e.g., IL-12), for developing into matured DCs (CD11c+CD80+CD86+MHCII expressing cells).143-149 The matured DCs or antigen pulsed DCs migrate to the nearby tumor draining lymph node and present processed antigen via MHCII to CD4+ T helper cells to initiate a Cytotoxic T Lymphocyte (CTL)-based antitumor immune response (Figure 5).149 Immune suppressive molecules on tumor cells, such as programmed death-ligand (PDL1 and PDL2), and T cells, such as cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1), suppress the activation of CTLs; thus, immune suppressive blockers, such as antibodies, need to be administered prior to NIR laser treatment.150-154


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Figure 5. Schematic representation of the light-triggered tumor ablation leads to domino effect of immune cells in the tumor microenvironment. 1) PDT/PTT laser treatment leads to release of tumor associated antigens (TAA), 2) circulating immature dendritic cells (iDCs) captures the TAA and process them for antigen presentation, 3) addition of DC maturating agents such as poly

I:C,

CpG

oligonucleotide,

R848,

R837,

IL-12,

IL-2,

enhances

the

CD11c+CD80+CD86+MHCII+ mature dendritic cells (mDCs), 4) mDCs or antigen pulsed DCs migrate to the tumor draining lymph node (TDLNs), 5) mDCs expressing MHCII loaded with processed antigen will present to CD4+ T helper cells (Th cells), 6) CD4+ Th cells activates



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other CD8+ T cells or cytotoxic T lymphocytes (CTLs), 7) CTLs releases cytotoxic granules like perforin, or induce Fas mediated cell death to the cancer cells. 8) activated Th cells and CTLs proliferate into memory Th cells and memory CTLs, memory Th cells again recognize antigen pulsed mDCs and stimulate memory CTLs to induce cell death to cancer cells.149-164 The final domino event depends on many factors to achieve complete tumor reduction and to initiate memory immune cells to prevent further tumor recurrence or metastasis. The first factor was the release of proinflammatory cytokines, such as IFN-γ, TNFα, IL-6, IL-1α, and IL-1β, from the ablated tumor tissues or immune cells such as Th lymphocytes, CTLs or NK cells.155-159 The second factor was the increase of the number of memory T cells with a reduction in Treg cells.160-162 Finally, the third factor was the efficient infiltration of T cells into the tumor microenvironment.163, 164 CO-DELIVERY AGENTS FOR ENHANCING THE IMMUNE RESPONSE IN TUMORS DURING PHOTOABLATION The photothermal ablation of solid tumors alone cannot improve therapeutic outcomes, but an immune stimulant can improve the anti-tumor effects through co-delivery. A pilot clinical trial of late-stage breast cancer patients treated by indocyanine green (ICG)-based laser irradiation along with glycolated chitosan-mediated immune stimulation improved the number of patients who experienced a partial response to the laser immunotherapy treatment.165 Korbelik et al. used serum vitamin D3-binding protein-derived macrophage-activating factor (DBPMAF) as an adjuvant for photofrin-based photodynamic therapy (PDT) in a mouse SCCVII tumor model.166 Photodynamic therapy created inflammation that initiated the recruitment of macrophages to the tumor site, but dead cells secreted immune suppressive factors that inhibited the action of the macrophage-mediated tumor killing.167 The vitamin D3-binding protein-derived macrophage20 ACS Paragon Plus Environment

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activating factor (DBPMAF) adjuvant prevented this immune suppression and enhanced immune potentiation at the tumor site.166

S. No

Immune agents

Immune response

1

CpG

TLR9-mediated

oligonucleotide

immune response

Immune response during

Ref.

phototherapy Enhanced

DC

maturation

(CD11b+CD80+) and CD8+ T cell proliferation induced by IFN-

168-

γ and CTL responses that were

170

more significant after PDT and CpG treatment. 2

R837

TLR7-mediated

DCs in TDLNs matured, and

immune response

proinflammatory cytokines, such 171as IL-12p70, IL-6, and TNFα, 173 were elevated in serum after PTT (or PDT co-treatment with R837).

3

LPS

TLR4-mediated

Splenic CD8α+ DCs targeting

immune response

only CD8+ T cells were enhanced after PTT with LPS-conjugated

174, 175

NPs. 4

Antibodies (Anti-PDL1

Blocking and immune-

CD8+

and

CD4+

T

cell

activation and proliferation were

176, 177



Anti-CTLA-4)

suppressive

enhanced

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after

PTT

co-

molecules such as administered with antibodies. PDL1 and CTLA4 5

Tropomyosin

Suppression

of

receptor kinase C transforming (TrkC) ligands

growth

During PDT, proinflammatory cytokines, such as IL-6, were

factor elevated, while anti-inflammatory 178

(TGF)-β signaling

cytokines, such as IL-4, IL-2, and TGF-β, MDSCs and Treg+ cells were suppressed.

Table

1:

Immune

agents

co-administered

with

photo-therapy

for

enhanced

photoimmunotherapy.

Another group of co-delivery agents are Toll-like receptor (TLR) activators, which play a major role in enhancing photoimmunotherapy in cancer. TLRs are immune recognition receptors that respond to a vast range of microbial components such as lipopolysaccharide (LPS), flagellin, single and double stranded RNA and unmethylated CpG oligonucleotide.179, 180 Their presence and signal transduction function in most immune and cancer cells make them a primary focus for immunotherapy.179 TLRs activate a cascade of molecules that are responsible for the activation of inflammatory responses.181 TLR-3,7/8, 9, 4 and 5 have major influence on the activation of proinflammatory immune cells such as Th1 cells, CD8+ T cells, NK cells and macrophages.182184

In phototherapy, PDT- or PTT-killed cells are taken up by dendritic cells and later presented

as tumor antigens to Th cells. However, this process requires the activation of TLRs for 22 ACS Paragon Plus Environment

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maturation, cytokine secretion and mobility. Xia et al. showed that as a TLR9 agonist, the CpG oligonucleotide showed enhanced verteporfin-PDT-mediated tumor reduction in a 4T1 breast cancer tumor model through the activation and maturation of CD11c+ DCs.168

NANOPARTICLE-BASED

PHOTOTHERMAL

AND

PHOTODYNAMIC

IMMUNOTHERAPY PTT or PDT kills cancer cells by using metal-, dye-, or carbon-based nanoparticles that have NIR absorbance and creates heat or reactive oxygen species in tumor cells; however, in addition to tumor killing, administering immune response-enhancing agents (e.g., adjuvants), cytokines and immune suppressive blockers is necessary, as they prevent tumor recurrence and metastasis and improve survival rates. Some of the nanoparticles used for PTT and PDT are listed in Table 1 along with immune-enhancing agents. S.No.

Nanoparticles

Immune agent

1

PLGA-ICG-

R837 adjuvant and Photothermal

R837

CTLA-4 antibody irradiation of the first blockade

Therapeutic outcome

References

tumor with subsequent

PTT CTLA-4

antibody

injection

completely

immune

171

therapy suppressed the growth of

second

tumor

inoculation. 2

Lipopolysacchar LPS

LPS-

and

PTT-

174



Page 24 of 73

ide

(LPS)-

mediated

coated

copper

release caused CD8α+

sulfide

(LPS-

DC

antigen

maturation

and

prevented spleen and

CuS)

liver metastasis. 3

CpG

complex CpG

chitosan-coated

Photothermal ablation

oligonucleotide

hollow copper-

and

TLR9-mediated

immune

activation 185

sulfide

significantly the

reduced

primary

and

distant tumors. 4

pH-sensitive

CTLA-4

PTT and anti-CTLA-4

Prussian blue

antibodies

prevented growth

tumor after

re176

challenge

and

increased the survival rate. 1

HK

peptide Ablated

PDT

functionalized

immune

graphene oxide antigen

therapy

loaded Photochlor

secreted

with tumor)

tumor Necrotic

4T1

cells

tumor caused

by

PDT

(necrotic enhanced

186

CD11c+/CD80+/CD8 6+

dendritic

cells,


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(HPPH)

which in turn more significantly activated CD4+ and CD8+ T cells

in

the

laser

irradiated tumor. 2

Upconversion

R837 adjuvant and DC maturation from

nanoparticles

CTLA-4 antibody PDT-caused

loaded

with blockade

necrotic

cells and R837 were

chlorin e6 and

able to activate and

R837

retain memory CD4+ and CD8+ T cells. CTLA-4

inhibited

172

Treg cell binding to mature

DCs.

treatment

The

efficiently

inhibited the growth of

distant

and

re-

challenged tumors. 3

Chlorin-based

Indoleamine

nanoscale

dioxygenase (IDO) enzyme increased T

2,3- Inhibiting

the

IDO

187 metal-organic framework

inhibitor

cell survival and the activation of T cells



(nMOF)

Page 26 of 73

after PDT irradiation. Enhanced

antitumor

immunity

occurred

based on B cell, α CD8+, and α CD4+ expansion. 4

Zn-

PD-L1 antibody

After efficient PDT

pyrophosphate

treatment, anti-PD-L1

(ZnP)

treatment

activated

nanoparticles

systemic

anti-tumor

loaded with the

immunity

photosensitizer

prevented distant and

pyrolipid

primary tumor growth.

188

and

Table 2: PTT- and PDT-based nanoparticles for cancer immunotherapy.

Nanoparticles for photothermal immunotherapy The photothermal ablation of tumors provides an opportunity for immune cells to gain access to the tumor microenvironment to improve the antitumor immune response. Photothermal irradiation in the presence of an adjuvant leads to the increased recruitment of lymphocytes.189 A long-term immune response can also be achieved by the presence of tumor antigen in blood serum, which gives rise to a prolonged immune response through the antibodies produced against a particular cancer.190, 191 Chen et al. has shown that ICG-based photothermal ablation along with 26 ACS Paragon Plus Environment

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the use of the immunoadjuvant glycated chitosan enhanced tumor selective antibodies in the sera of rats.192 Combinatorial strategies of photothermal therapy and chemotherapy in cancer treatment have been shown to induce synergistic efficacy that are greater compared to either individual noninvasive treatment regime;193-196 however, this strategy failed to prevent the recurrence of tumors in non-immunogenic cancers such as pancreatic ductal adenocarcinoma (PDAC) and breast cancer.197 Hence, the additional administration of immune activating agents, such as CpG DNA, adjuvants, antibodies and TLR activators, could enhance the therapeutic efficacy of these combinatorial treatments.198 Gold nanoparticles have unique optical and structural properties that can be fine-tuned for photoimmunotherapy.199 Yata et al. showed that a CpG-encoded hexapodlike structured DNA-conjugated gold nanoparticle hydrogel improved photothermal ablation and increased splenocyte IFN-γ production and serum IgG levels against the OVA antigen on EG7OVA tumors.200 Here, the IFN-γ production has direct negative effect on cancer cell proliferation, angiogenesis and positive effect on apoptosis and MHC class I expression in antigen presenting cells (APCs).201,

202

Additionally, circulating IgG levels against cancer

specific antigens act as mediator for directing natural killer (NK) cells and CTLs to eradicate tumor cells.203, 204 Immune checkpoints are co-stimulatory and inhibitory molecules regulates the immune system activation and promotes self-tolerance. Immune checkpoint molecules like CTLA-4, PD-1 and PDL-1/2 were considered as key therapeutic targets in anti-cancer immunotherapy.154 CTLA-4 and PD-1 checkpoints are expressed by cancer cells as well as in

TICs in tumor

microenvironment and suppresses the T cell immune function against tumor cells.205, 206 Hence, PTT effect along with checkpoint blockade could improve the T cells to function against cancer 27 ACS Paragon Plus Environment


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cells more effectively. As shown in Figure 6 (i), Chen et al. proved that PLGA-loaded ICG and R837 adjuvant enhanced photothermal immunotherapy along with CTLA-4 blockade in a 4T1 tumor model.171 Here, CD4+ FOXP3+ Treg cells were suppressed and CD8+ T cell proliferation was increased in the PTT-treated and anti-CTLA-4-administered 4T1 tumor mice.171 Tumor growth did not occur upon rechallenge in the photoimmunotherapy model, and an improved long-term immune memory effect was observed.171 Similarly, Cano-Mejia et al. intratumorally injected Prussian blue and intraperitoneally injected anti-CTLA-4 antibodies in a neuroblastoma mouse model.207 Photoablation of the tumor caused lymphocytes and other T cells to infiltrate, which in turn produced an immune response against the tumor; furthermore, the i.p. administration of anti-CTLA4 blocked the anti-immune response against the tumor. TLR-9 based adjuvants activates circulating dendritic cells and induce secretion of proinflammatory cytokines like TNFα and IL-12, that in turn activates CTLs and Th1 cells for anticancer effect.208, 209 Here, Guo et al. developed photoimmunotherapy-based nanoparticles that consisted of chitosan-coated hollow copper sulfide nanoparticles co-complexed with CpG oligonucleotide via electrostatic interactions with the chitosan surface.185 Photothermal ablation with hollow copper sulfide nanoparticles and TLR9 adjuvant increased antigen production, which in turn improved the maturation of APCs, such as dendritic cells (CD11c+ CD86+), the proliferation of CD8+ T cells and the production of inflammatory cytokines, such as IFN-γ, in secondary immune organs such as draining lymph nodes and the spleen.185 Li et al. developed an IR-7 fluorophore-loaded liposome coated with hyaluronic acid-conjugated CpG oligonucleotide (IR-7-lipo/HA-CpG) for photothermal-mediated immunotherapy in a CT26 colon cancer model.171 Tumor cell debris from ablated tumors and TLR9 adjuvant stimulated precursor


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dendritic cells to secrete proinflammatory cytokines such as IL-6, TNFα, and IL-12, which caused more naïve T cells to be differentiated into activated T cells and memory T cells.210 Recently, studies have been done to explain the role of immune system in nanoparticle based photothermal-chemotherapy. Nam et al., has used DOX loaded polydopamine coated surfactant free gold nanostar for photothermal-chemotherapy in xenograft and metastatic mouse model. 211 Here, it was observed that effective tumor ablation has led to release of tumor antigens, that are later uptaken by the circulating immature DCs. Later, the matured DCs has activated the CTLs, NK cells and elevated the augmentation of immune activation for eliminating distinct tumor or preventing tumor recurrence. Although, the study has shown the reduction of primary and contralateral tumor growth, there are still an slight rise in the tumor volume after 25 days, that signifies the possibility for tumor recurrence. Therefore, it is recommended that photothermal therapy or photo-chemotherapy should be supported with the immune enhancing agents like adjuvants, or immune suppressive blockers for enhanced photothermal immune response against cancer.



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Figure 6: Photothermal-mediated immunotherapy using nanoparticle delivering chemo-drugs or adjuvant. i) Formulation of PLGA-ICG-R837 nanoparticles and their immune-stimulation abilities. Reprinted from ref 171 under a Creative Commons Attribution 4 International License https://creativecommons.org/licenses/by/4.0/ Copyright 2016 Chen et al. ii) Schematic presentation of development of spiky gold nanoparticles (SGNPs) coated with PDA 30 ACS Paragon Plus Environment

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(SGNP@PDA) for combination chemo-photothermal therapy triggered potent anti-tumor immunity in vivo. Reprinted from ref 211 under a Creative Commons Attribution 4 International License https://creativecommons.org/licenses/by/4.0/ Copyright 2018 Nam et al. Immune cells can also assist nanoparticles to be delivered specifically to the tumor site and help in photothermal mediated tumor killing. PTT based nanoparticles can be loaded into T cells without affecting the functions such as tumor cell infiltration and cytokine secretion.119 Burga et al. conjugated Prussian blue nanoparticles onto the surface of CTLs via a biotin-avidin conjugation method for immune-mediated photothermal therapy.212 This research strategy was focused on treating virus-associated malignancies such as Epstein–Barr virus (EBV); consequently, its efficiency in delivering photoimmuno-ablation in human clinical trials cannot be addressed until a complete in vivo study on these cell-based nanoparticles is completed. Carbon-based nanoparticles are quite prominent in cancer immunology due to their ability to induce inflammation. Wang et al. studied the immunological response triggered by PEGylated single-walled carbon nanotubes (SWCNTs) in normal mice according to concentration and time.213 The photothermal ablation of tumors in conjunction with the administration of antiCTLA-4 antibodies was shown to significantly increase cytotoxic T cells while reducing Treg cells,213 which was attributed to the rejection of second tumor growth as well as the poor survival of metastatic cells released from the primary tumor. One of the key findings of this study was that the maturation of dendritic cells and the production of cytokines, such as IL-1β, IL-12p70, TNFα, and IL-6, were significantly increased upon treatment with peg-SWCNTs even without photothermal ablation,213 suggesting that carbon-based nanoparticles are quite unique and interesting for photothermal-based cancer immunotherapy applications.



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Tian et al. developed polymer-based photothermal agents and studied the immunological responses that occurred after photothermal ablation.214 The nanoparticles consisted of a polypyrrole shell over a polydopamine core loaded with Fe3+ ions and stabilized with sodium dodecyl sulfate (SDS) and polyvinyl alcohol (PVA).214 Photothermal ablation induced the maturation of DCs in lymph nodes and increased the production of serum cytokines such as IL12, IL-1β, IL-6 and TNF-α.214 Similarly, pegylated MoS2 nanosheets conjugated with CpGs also improved photothermal therapy by increasing DC maturation as well as TNFα production.215 As it was previously discussed, laser irradiation on the tumor accumulated with PTT based nanoparticles induces the infiltration of lymphocytes and other antigen presenting cells for clearance of cell debris. Even though, a temporary immune response against the cancer cells have been initiated, a sustained tumor growth retardation will occur for short period time. The non-ablated cancer cells will secrete the immune suppressive factors and therefore block the anti-cancer effect of the activated lymphocytes and antigen presenting cells. overall, in order to overcome this effect, the PTT based nanoparticle should be designed along with following agents: a) immune checkpoint blockers like CTLA-4, PDL-1 or PD-1 antibodies, b) TLR based adjuvants like CpG oligonucleotide or R837, c) tumor penetrating peptides for uniform distribution of nanoparticle even in deep tumor, and d) proinflammatory cytokines like IL-2, IL12, or IFNγ.

Nanoparticles for photodynamic immunotherapy Antigen presenting cells like macrophages and DCs respond to necrotic tumor cells. Macrophages stimulated with necrotic tumor cells increased DC maturation, IFN-γ and IL-2 production that enhanced splenocyte mediated killing of cancer cells.216 Therefore, Yu et al. 32 ACS Paragon Plus Environment

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prophylactically vaccinated mice via the injection of necrotic 4T1 cells treated with HK peptidefunctionalized graphene oxide nanoparticles loaded with photosensitizer and Photochlor [2-(1hexyloxyethyl)-2-divinyl pyropheophorbide-alpha] (HPPH) and irradiated them with a PDT laser.186 This approach was found to prevent the further growth and metastasis of subcutaneously and intravenously injected 4T1 cells in the system. Further immune studies elucidated that the necrotic 4T1 cells were taken up by circulating dendritic cells, which further matured (CD11c+, CD80+high, CD86+high) and activated other CD8+ and CD4+ T cells.186 Although PDT efficiently triggers anticancer immune responses, the responses are strongly opposed by immune suppressive elements, such as PD-1, PDL1/2, and CTLA4, expressed on the surface of both cancer cells and tumor-associated immune cells. Interestingly, Gao et al. blocked the PD-1 receptors by injecting anti-PD1 antibodies after performing IRDye700-streptavidinbiotin-HK peptide (DSAB-HK)-based PDT treatment in a 4T1 tumor model.217 The PD-1 blockade prevented immunosuppression by blocking contact between the cancer cells and immune cells such as CD4+ T cells and CD11c+ DCs.218-221 Therefore, enhanced PDT-mediated immunotherapy in cancer will be easily achieved using this technique. Targeting the mitochondria and initiating photothermal ablation lead to the combined effect of PTT and PDT in cancer cells. Recently, Wu et al. developed mitochondrial targeting graphene oxide loaded with IR820 dye and CpG via lipid-PEG for combined PDT/PTT immunotherapy in an EMT6 tumor model.222 The TLR9 adjuvant CpG oligo enhanced the anti-tumor immune response via the maturation of dendritic cells as well as the secretion of TNFα and IL-6.222 Targeting universal antigens, such as telomerase reverse transcriptase (hTERT), p53interacting protein MDM2, and cytochrome P450 isoform 1B1, which are expressed universally only in tumors and not in healthy tissues, enhances the chances of activating the high affinity T 33 ACS Paragon Plus Environment


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cell pool in the tumor microenvironment.223 Zhen et al. performed targeted killing of fibroblastactivation protein (FAP)-overexpressing carcinoma-associated fibroblasts (CAFs) using ZnF16Pc-loaded ferritin (Z@FRT) nanoparticles.224 Reducing the CAFs improved CD8+ T cell infiltration and enhanced the PDT-mediated anti-tumor immune response in 4T1 tumor mice.224 Similar to PTT based immunotherapy, PDT based immunotherapy can also be supported with immune checkpoint blockers and TLR based adjuvants. As shown in Figure 7 (i), Xu et al. used upconversion nanoparticles to deliver chlorin e6 (Ce6) and R837 for photodynamic immunotherapy using CTLA4 blockade in a CT26 colon cancer model.172 The CTLA-4 blockade enhanced the APC presentation of antigen to T cells by blocking the activation of Treg cells and resulted in improved suppression of distinct and rechallenged tumor growth.172 Also recently, Song et al. integrated 1-methyltryptophan (MT-1) as an IDO small molecule inhibitor into a micellar nanoparticle system to enhance CD8+ activation and proliferation in a metastatic CT26 tumor model after photosensitizer-based PDT [Figure 7(ii)].225 The immune blockade agent supported primary tumor growth retardation and prevented lung metastasis.225 PDT are considered as effective as PTT in tumor destruction, its efficacy has to be still improved with proper design of nanoparticle in such a way that it a) penetrates deep tumor tissue, b) supplied with oxygen for free radical generation and c) low photobleaching. Similar to PTT immunotherapy, PDT should also be assisted with immune enhancing agents. Although, basic mechanism on PDT triggered immune response should be studied in detail for clearly understanding and assessing the need for additional therapeutic agents.


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Figure 7: Photothermal-mediated immunotherapy using nanoparticles and adjuvants. i) Scheme summarizing the mechanisms of NIR-mediated PDT combined with CTLA-4 checkpoint blockade for cancer immunotherapy and immune memory effects after UCNP-Ce6-R837-based PDT. Reproduced with permission from ref 172. Copyright 2017 American Chemical Society. ii) Schematic representation of the structure of the chimeric peptide PpIX-1MT. PpIX-1MT nanoparticles accumulated in the tumor area via the EPR effect, where they activated CD8+ T cells through a series of cascade activations, effectively inhibiting the primary tumor as well as lung metastasis. Reproduced with permission from ref 225. Copyright 2018 American Chemical Society.

CONCLUSION Combinatorial treatment strategies for cancer involve the implementation of systemic and external therapies to achieve improved therapeutic outcomes. Among these combinations, phototherapy demonstrated better performance in eliminating tumors, though it requires certain additional treatments for aggressive tumors and long-term therapeutic efficacy. Hence, photoimmunotherapy will be effective for both indolent and aggressive tumors, and nanoparticlebased photoimmunotherapy will provide better therapeutic effects and have the potential to treat large tumors. The therapeutic effects of photoimmunotherapy will be better than those of other systemic and external therapies against aggressive tumors. The co-administration of immune enhancers and immune suppressive blockers augments photoimmunotherapy. Furthermore, phototherapy enhances tumor antigen release better than conventional chemotherapies. Therefore, future nanoparticle-based phototherapies will combine NIR-absorbing materials and immune-enhancing agents for optimal tumor management. 36 ACS Paragon Plus Environment

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FUTURE PERSPECTIVES During phototherapy, the constant release of tumor antigen for APC maturation are an important factor for immune-mediated anticancer effects.226 For a large tumor, a single laser dose are not sufficient for complete tumor killing, making the likelihood of tumor relapse in the laserirradiated area higher.227 Hence, repeated laser treatment of the tumor could enhance antigen production and simultaneously improve the immune response.228 The effect of repeated laser doses depends on the accumulation and stability of the PTT/PDT agent in the tumor. For more efficient photoimmunotherapy, supplements of immune suppressive blockers, such as anti-PDL1, PDL2 and CTLA-4, need to be administered given that immune suppressive elements block the phototherapy-mediated immune response domino effect against cancer cells. 176, 177, 187, 188, 217, 229 During PTT or PDT, the tumor-draining lymph nodes should be protected from heat and ROS because the immune responses from adjacent lymph nodes are faster and more efficient. During phototherapy, the non-ablated cancer cells escape the immune system and therefore causes metastasis. This limitation can only be overcome by combining phototherapy with chemo or immunotherapy. Especially in photoimmunotherapy, the antigen presenting cells will be supported with immune enhancers, that in turn creates a chain of immune response and form a memory immune cells against the non-ablated tumor cells. Although, the major challenges faced in human clinical trials are application of laser to the small tumor or metastasized tumor in different organs, since it can be applicable for only superficial cancers like melanoma, osteosarcoma, ameloblastoma and squamous cell carcinoma. Recent studies are focused on ablating tumors residing in the deep organs without damaging the healthy tissues. Tan et al., has 37 ACS Paragon Plus Environment


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delivered layered MoS2 hollow spheres directly into the orthotropic liver tumor in VX2 rabbit model via transarterial administration and then irradiated with 808 nm laser.230 The temperature rise of 55°C was observed only in the tumor site and CT images revealed that shrinking of tumor in the liver was significantly higher.

230

In other case, Bagley et al., has systemically

administered PEGylated gold nanorod (PEG-NRs) and later used a silica rod implant to deliver NIR light specifically to irradiated the PEG-NRs accumulated in the orthotropic ovarian cancer.231 Apart from the ovarian tumor tissue, the other peritoneal organ remained healthy and safe after NIR laser irradiation.231

Although, it needs to be further accessed for clinical

application. Overall, preclinical studies such as these enhanced the chances for ablation of deep organ tumors in future cancer patients. Hence, the future development of photo-immunotherapy should be focused on designing advanced tools for delivering NIR light or nanoparticles to the deep organ tumors, and developing nanoparticle for delivering tumor specific immune enhancers in order to enhance photothermal-mediated immunotherapy in the clinical trials. AUTHOR INFORMATION Corresponding Author In-Kyu Park* Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju 61469, South Korea. E-mail: [email protected] Chong-Su Cho* Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 08826, South Korea. E-mail: [email protected]


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Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENTS This work was financially supported by Basic Science Research Program (No. 2016R1A2B4011184 & 2016K2A9A1A06921661) and the Bio & Medical Technology Development Program (No. NRF-2017M3A9F5030940 and NRF-2017M3A9E2056374) through the National Research Foundation of Korea (NRF) funded by the Korean government, MSIP; and the Pioneer Research Center Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (2014M3C1A3053035). IKP also acknowledges the financial support from a grant (HCRI 17901-22) Chonnam National University Hwasun Hospital Institute for Biomedical Science.

ABBREVIATIONS AMF, alternating magnetic field; BRET, Bioluminescence resonance energy transfer; BN, Bombesin; BPQDs, black phosphorous quantum dots; CAFs, carcinoma-associated fibroblasts; CCL, chemokine (C-C motif) ligands; CCL17, CC chemokine ligand 17; CCL22, CC chemokine ligand 22; CCL24, CC chemokine ligand 24; CCL1, CC chemokine ligand 1; CD, Cluster of differentiation; CTLs, cytotoxic T lymphocytes; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DBPMAF, vitamin D3-binding protein-derived macrophage-activating; DCs, dendritic cells; GO, graphene oxide; DOX, doxorubicin; EPR, enhanced permeability retention; FAP, fibroblast-activation protein; forkhead box P3; FOXP3, FRET, Förster resonance energy transfer; 39 ACS Paragon Plus Environment


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HIF-1α , human inducing factor 1 alpha; HIFU, high intensity focused ultrasound; HPPH, HK peptide functionalized graphene oxide loaded with Photochlor [2-(1-hexyloxyethyl)-2-divinyl pyropheophorbide-alpha]; hTERT, human telomerase reverse transcriptase; ICG, indocyanine green; IDO, Indoleamine 2,3-dioxygenase; IFN-γ, interferon gamma; IL-1β, interleukin 1 beta; IL-2, interleukin 2; IL-4, interleukin 4; IL-6, interleukin 6;

IL-10, interleukin 10; IL-12,

interleukin 12; IL-12p70, interleukin 12p70; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; MDSCs, myeloid derived suppressor cells; MHC II, major histocompatibility complex II; miRNA, microRNA; MRI, magnetic resonance imaging; MT-1, 1-methyltryptophan; NIR, near-infrared; NK, natural killer; NO, nitric oxide; PD-1, programmed cell death protein-1; PDL1, programmed death-ligand 1, PDL2, programmed death-ligand 2; PDT, photodynamic; PEG, polyethylene glycol; PLGA, poly(lactic-co-glycolic acid); PTT, photothermal; RNA, ribonucleic acid; PVA, polyvinyl alcohol; ROS, reactive oxygen species; siRNA, silencing RNA; S1P, sphingosine-1-phosphate; SDS, sodium dodecyl sulfate; SPIONs, superparamagnetic iron oxide nanoparticles; SWCNTs, single-walled carbon nanotubes; TADs, tumor-associated dendritic cells; TAMs, tumor-associated macrophages, TaS2, tantalum sulfide; TDLNs, tumor draining lymph nodes; TICs, tumor-associated immune cells; TLR, Toll-like receptor; TGF-β, transforming growth factor beta; TNFα, tumor necrosis factor alpha; Treg, regulatory T lymphocyte; TrkC, Tropomyosin receptor kinase C; UCNP, upconversion nanoparticle; ZnP, Zn-pyrophosphate. REFERENCES 1.

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