Viewpoint Cite This: Biochemistry XXXX, XXX, XXX−XXX
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YTHDF1 Control of Dendritic Cell Cross-Priming as a Possible Target of Cancer Immunotherapy Daniel J. Kim† and Akiko Iwasaki*,†,‡,§ †
Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06519, United States Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520, United States § Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, United States ‡
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Neoantigens (antigens created by mutations in cancer) enable CTLs to recognize tumors as “non-self” for destruction. A key challenge in immunooncology is converting cold tumors into hot tumors that can be treated by checkpoint blockade therapy. To become killer cells, naive CD8+ T cells must first be primed against neoantigens by dendritic cells (DCs). After phagocytosing dying tumor cells, DCs can either degrade tumor antigens in the phagosome for presentation on MHC class II molecules (stimulating CD4+ T cells) or transport the antigens to cytosol for MHC class I presentation (stimulating CD8+ T cells) (Figure 1). The relative amount of antigens delivered to the MHC class II “direct presentation” pathway versus the MHC class I “cross-presentation” pathway is partially dictated by the phagosomal degradative capacity.3
n most eukaryotes, m6A methylation is the most abundant internal modification found in mRNA.1 YTHDF1 is a member of the YTH domain family, which binds m6A and modulates translation. In the February issue of Nature, Han et al. describe a new role for YTHDF1 in regulating the cytotoxic T lymphocyte response to tumor antigens.2 The advent of checkpoint inhibition immunotherapy has benefited unprecedented numbers of cancer patients. Drugs like pembrolizumab (antibody against PD-1) release the inhibition placed on CD8+ cytotoxic T lymphocytes (CTLs) by tumor cells through the PD-1/PD-L1 axis. The success of this therapeutic strategy relies on “hot” tumor microenvironments with a high infiltration of CTLs already present at the baseline. In contrast, “cold” tumors, lacking significant immune infiltration, do not respond to immunotherapies.
Figure 1. YTHDF1 regulates DC cross-presentation of extracellular antigens. After DCs phagocytose extracellular proteins, cathepsins either degrade these proteins or help process them for direct presentation on MHC class II molecules to CD4+ T cells (left panel). Proteins that are not degraded can also be transported to the cytosol to be processed by proteasomes and later loaded onto MHC class I molecules for cross-presentation to CD8+ T cells (right panel). By promoting translation of m6A-modified cathepsin mRNA, YTHDF1 enhances antigen degradation in the phagosome and limits cross-presentation of neoantigens in DCs. Received: March 8, 2019
© XXXX American Chemical Society
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DOI: 10.1021/acs.biochem.9b00200 Biochemistry XXXX, XXX, XXX−XXX
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Biochemistry
Figure 2. Anti-YTHDF1 therapy can synergize with immune checkpoint blockade by increasing the number of CTLs in the tumor. (A) Active YTHDF1 promotes translation of cathepsins, which degrade neoantigens and decrease cross-priming of CTLs, leading to a “cold” tumor. Once in the tumor, CTLs are inhibited by PD-L1 expression on cancer cells. (B) With combinatorial therapy, YTHDF1 inhibition can increase the number of primed CTLs in the tumor, and anti-PD1/anti-PD-L1 treatment can increase CTL effector functions.
stimulating them to home to tumor cells (Figure 2B). The nowhot tumor is a prime candidate for checkpoint inhibition, which releases the brakes placed on effector T cells. By enhancing two distinct steps of antitumor T cell activation, priming T cells and releasing their inhibition from PD-L1, this combinatorial approach may one day synergistically reap the benefits of both therapies.
Han et al. revealed that YTHDF1 enhances translation of mRNA encoding cathepsins (lysosomal proteases that degrade antigens in phagosomes). Without YTHDF1, cathepsin translation is diminished, favoring antigen cross-presentation and promoting more killer CTL responses against neoantigens (Figure 1). Thus, these results indicate a specificity for YTHDF1 in regulating lysosomal functions in DCs. Notably, in other tissues like hippocampal neurons, YTHDF1 promotes translation of m6A-modified mRNA, facilitating learning and memory.4 Future studies may reveal cell-type specific regulatory targets of m6A-modified RNA by YTHDF1 and other m6A effector molecules. The study also reveals an exciting new avenue for therapeutic intervention, one that should help convert “cold” tumors into “hot” ones, which can then be targeted with checkpoint inhibition. Before this potential can be realized, however, several hurdles must be overcome. First, because YTHDF1 controls the expression of many target genes, identifying a more focused therapeutic target is necessary to minimize potential off-target toxicity. Second, YTHDF1 inhibition presumably increases cross-presentation of self-antigens alongside neoantigens, thereby increasing risk for autoimmunity. Third, diverting the immune response away from the CD4+ T cell response (Figure 1) may have unintended consequences, such as an impaired defense against bacterial and fungal pathogens (which require a specialized CD4+ T cell response) and lack of robust antibody responses (which requires helper function of CD4+ T cells) to fight infectious agents in general. Even with such obstacles, the potential synergistic interactions between this novel strategy and immune checkpoint inhibition are promising. In cold tumors, a few primed CTLs infiltrate the tumor because a low mutational burden or excessive degradation in DC phagosomes (Figure 2A) results in a lack of neoantigens. In the cases of excessive degradation, YTHDF1 inhibition may preserve more neoantigens for cross-presentation to CTLs,
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Akiko Iwasaki: 0000-0002-7824-9856 Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Yue, Y., Liu, J., and He, C. (2015) RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 29, 1343−1355. (2) Han, D., Liu, J., Chen, C., Dong, L., Liu, Y., Chang, R., Huang, X., Liu, Y., Wang, J., Dougherty, U., Bissonnette, M. B., Shen, B., Weichselbaum, R. R., Xu, M. M., and He, C. (2019) Anti-tumour immunity controlled through mRNA m(6)A methylation and YTHDF1 in dendritic cells. Nature 566, 270−274. (3) Joffre, O. P., Segura, E., Savina, A., and Amigorena, S. (2012) Cross-presentation by dendritic cells. Nat. Rev. Immunol. 12, 557−569. (4) Shi, H., Zhang, X., Weng, Y. L., Lu, Z., Liu, Y., Lu, Z., Li, J., Hao, P., Zhang, Y., Zhang, F., Wu, Y., Delgado, J. Y., Su, Y., Patel, M. J., Cao, X., Shen, B., Huang, X., Ming, G. L., Zhuang, X., Song, H., He, C., and Zhou, T. (2018) m(6)A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature 563, 249−253.
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DOI: 10.1021/acs.biochem.9b00200 Biochemistry XXXX, XXX, XXX−XXX
