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Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells

Author

Listed:
  • Mahesh Pandit

    (Yeungnam University)

  • Yun-Seo Kil

    (Yeungnam University)

  • Jae-Hee Ahn

    (Kangwon National University)

  • Ram Hari Pokhrel

    (Yeungnam University)

  • Ye Gu

    (Yeungnam University)

  • Sunil Mishra

    (Yeungnam University)

  • Youngjoo Han

    (Kangwon National University)

  • Yung-Taek Ouh

    (Kangwon National University)

  • Ben Kang

    (Kyungpook National University)

  • Myeong Seon Jeong

    (Korea Basic Science Institute (KBSI)
    Kangwon National University)

  • Jong-Oh Kim

    (Yeungnam University)

  • Joo-Won Nam

    (Yeungnam University)

  • Hyun-Jeong Ko

    (Kangwon National University)

  • Jae-Hoon Chang

    (Yeungnam University)

Abstract

Programmed cell death protein 1 (PD-1), expressed on tumor-infiltrating T cells, is a T cell exhaustion marker. The mechanisms underlying PD-1 upregulation in CD4 T cells remain unknown. Here we develop nutrient-deprived media and a conditional knockout female mouse model to study the mechanism underlying PD-1 upregulation. Reduced methionine increases PD-1 expression on CD4 T cells. The genetic ablation of SLC43A2 in cancer cells restores methionine metabolism in CD4 T cells, increasing the intracellular levels of S-adenosylmethionine and yielding H3K79me2. Reduced H3K79me2 due to methionine deprivation downregulates AMPK, upregulates PD-1 expression and impairs antitumor immunity in CD4 T cells. Methionine supplementation restores H3K79 methylation and AMPK expression, lowering PD-1 levels. AMPK-deficient CD4 T cells exhibit increased endoplasmic reticulum stress and Xbp1s transcript levels. Our results demonstrate that AMPK is a methionine-dependent regulator of the epigenetic control of PD-1 expression in CD4 T cells, a metabolic checkpoint for CD4 T cell exhaustion.

Suggested Citation

  • Mahesh Pandit & Yun-Seo Kil & Jae-Hee Ahn & Ram Hari Pokhrel & Ye Gu & Sunil Mishra & Youngjoo Han & Yung-Taek Ouh & Ben Kang & Myeong Seon Jeong & Jong-Oh Kim & Joo-Won Nam & Hyun-Jeong Ko & Jae-Hoon, 2023. "Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38316-9
    DOI: 10.1038/s41467-023-38316-9
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    References listed on IDEAS

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    1. Yingjie Bian & Wei Li & Daniel M. Kremer & Peter Sajjakulnukit & Shasha Li & Joel Crespo & Zeribe C. Nwosu & Li Zhang & Arkadiusz Czerwonka & Anna Pawłowska & Houjun Xia & Jing Li & Peng Liao & Jiali , 2020. "Cancer SLC43A2 alters T cell methionine metabolism and histone methylation," Nature, Nature, vol. 585(7824), pages 277-282, September.
    2. Minkyung Song & Tito A. Sandoval & Chang-Suk Chae & Sahil Chopra & Chen Tan & Melanie R. Rutkowski & Mahesh Raundhal & Ricardo A. Chaurio & Kyle K. Payne & Csaba Konrad & Sarah E. Bettigole & Hee Rae , 2018. "IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity," Nature, Nature, vol. 562(7727), pages 423-428, October.
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