2. Academic Validation
  3. Targeting P4HA1 promotes CD8+ T cell progenitor expansion toward immune memory and systemic anti-tumor immunity

Targeting P4HA1 promotes CD8+ T cell progenitor expansion toward immune memory and systemic anti-tumor immunity

  • Cancer Cell. 2024 Dec 23:S1535-6108(24)00476-8. doi: 10.1016/j.ccell.2024.12.001.
Shijun Ma 1,  Li-Teng Ong 1,  Zemin Jiang 1,  Wee Chyan Lee 1,  Puay Leng Lee 1,  Mubaraka Yusuf 1,  Henrik J Ditzel 2,  Yulan Wang 3,  Qingfeng Chen 4,  Wenyu Wang 5,  Xiaojian Wu 5,  Ern Yu Tan 6,  Qiang Yu 7
Affiliations

Affiliations

  • 1 Genome Institute of Singapore, Agency for Science, Technology, and Research (A(∗)STAR), 60 Biopolis Street, Singapore.
  • 2 Department of Oncology, Odense University Hospital and Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • 3 Singapore Phenome Center, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
  • 4 Institute of Molecular and Cellular Biology, A(∗)STAR, Biopolis, Singapore.
  • 5 The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 6 Institute of Molecular and Cellular Biology, A(∗)STAR, Biopolis, Singapore; Department of General Surgery, Tan Tock Seng Hospital and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
  • 7 Genome Institute of Singapore, Agency for Science, Technology, and Research (A(∗)STAR), 60 Biopolis Street, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore. Electronic address: yuq@gis.a-star.edu.sg.
PMID: 39729997 DOI: 10.1016/j.ccell.2024.12.001
Abstract

Successful immunotherapy relies on both intratumoral and systemic immunity, which is yet to be achieved for most patients with Cancer. Here, we identify P4HA1, encoding prolyl 4-hydroxylase 1, as a crucial regulator of CD8+ T cell differentiation strongly upregulated in tumor-draining lymph nodes (TDLNs) and hypoxic tumor microenvironment. P4HA1 accumulates in mitochondria, disrupting the tricarboxylic acid (TCA) cycle through aberrant α-ketoglutarate and succinate metabolism, promoting mitochondria unfitness and exhaustion while suppressing progenitor expansion. Targeting P4HA1 enhances both adoptive and endogenous TCF1+ CD8+ T progenitor expansion while mitigating the development of exhaustion in the tumor, TDLN, and blood, enabling a notable and durable systemic anti-cancer immunity. We propose that P4HA1 induction in CD8+ T cells in Cancer orchestrates an immune-escape program, offering a T cell-directed target for system immunotherapy in solid tumors.

Keywords

CAR T cells; P4HA1; PD-1; T cell exhaustion; T cell memory; cancer immunotherapy; hypoxia; mitochondria; solid tumors; systemic immunity.

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