T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy
Fumihiro Fujiki, Soyoko Morimoto, Akiko Katsuhara, Akane Okuda, Saeka Ogawa, Eriko Ueda, Maki Miyazaki, Ayako Isotani, Masahito Ikawa, Sumiyuki Nishida, Hiroko Nakajima, Akihiro Tsuboi, Yoshitaka Oka, Jun Nakata, Naoki Hosen, Atsushi Kumanogoh, Yusuke Oji, Haruo Sugiyama
Abstract
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.