Frontiers in Immunology (Jun 2022)

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,
  • Ayako Isotani,
  • Masahito Ikawa,
  • Sumiyuki Nishida,
  • Hiroko Nakajima,
  • Akihiro Tsuboi,
  • Yoshihiro Oka,
  • Yoshihiro Oka,
  • Yoshihiro Oka,
  • Jun Nakata,
  • Naoki Hosen,
  • Naoki Hosen,
  • Atsushi Kumanogoh,
  • Atsushi Kumanogoh,
  • Yusuke Oji,
  • Haruo Sugiyama

DOI
https://doi.org/10.3389/fimmu.2022.935465
Journal volume & issue
Vol. 13

Abstract

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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.

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