T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy

Frontiers in Immunology

Naoki Hosen¹  Fumihiro Fujiki²  Haruo Sugiyama²  Hiroko Nakajima²  Akihiro Tsuboi³  Soyoko Morimoto⁴  Yusuke Oji⁵  Jun Nakata⁵  Masahito Ikawa⁶  Akiko Katsuhara⁷  Saeka Ogawa⁷  Akane Okuda⁷  Maki Miyazaki⁷  Eriko Ueda⁷  Atsushi Kumanogoh⁸  Yoshihiro Oka⁸  Sumiyuki Nishida⁹  Ayako Isotani^1,10 

[1] 0Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Suita, Japan;Department of Cancer Immunology, Graduate School of Medicine, Osaka University, Suita, Japan;Department of Cancer Immunotherapy, Graduate School of Medicine, Osaka University, Suita, Japan;Department of Cancer Stem Cell Biology, Graduate School of Medicine, Osaka University, Suita, Japan;Department of Clinical Laboratory and Biomedical Sciences, Graduate School of Medicine, Osaka University, Suita, Japan;Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Japan;Department of Functional Diagnostic Science, Graduate School of Medicine, Osaka University, Suita, Japan;Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan;Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan;Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Japan;

关键词: vitamin A;    RDH10;    memory T cell;    retinoic acid;    cancer immunotherapy;    vitamin A metabolism;   

DOI  :  10.3389/fimmu.2022.935465

来源: DOAJ

【 摘 要 】

Memory T cells play an essential role in infectious and tumor immunity. Vitamin A metabolites such as retinoic acid are immune modulators, but the role of vitamin A metabolism in memory T-cell differentiation is unclear. In this study, we identified retinol dehydrogenase 10 (Rdh10), which metabolizes vitamin A to retinal (RAL), as a key molecule for regulating T cell differentiation. T cell-specific Rdh10 deficiency enhanced memory T-cell formation through blocking RAL production in infection model. Epigenetic profiling revealed that retinoic acid receptor (RAR) signaling activated by vitamin A metabolites induced comprehensive epigenetic repression of memory T cell-associated genes, including TCF7, thereby promoting effector T-cell differentiation. Importantly, memory T cells generated by Rdh deficiency and blocking RAR signaling elicited potent anti-tumor responses in adoptive T-cell transfer setting. Thus, T cell differentiation is regulated by vitamin A metabolism and its signaling, which should be novel targets for memory T cell-based cancer immunotherapy.

【 授权许可】

Unknown