2. Academic Validation
  3. PA suppresses antitumor immunity of T cells by disturbing mitochondrial activity through Akt/mTOR-mediated Ca2+ flux

PA suppresses antitumor immunity of T cells by disturbing mitochondrial activity through Akt/mTOR-mediated Ca2+ flux

  • Cancer Lett. 2024 Jan 28:581:216511. doi: 10.1016/j.canlet.2023.216511.
Shishuo Sun 1,  Heng Xu 2,  Wanxin Zhao 2,  Qihong Li 2,  Yifan Yuan 2,  Guopeng Zhang 2,  Shuyu Li 2,  Bixi Wang 2,  Wei Zhang 2,  Xiaoge Gao 1,  Junnian Zheng 3,  Qing Zhang 4
Affiliations

Affiliations

  • 1 Cancer Institute, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
  • 2 Cancer Institute, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
  • 3 Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China. Electronic address: [email protected].
  • 4 Cancer Institute, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China. Electronic address: [email protected].
PMID: 38013049 DOI: 10.1016/j.canlet.2023.216511
Abstract

Deciphering the mechanisms behind how T cells become exhausted and regulatory T cells (Tregs) differentiate in a tumor microenvironment (TME) will significantly benefit Cancer Immunotherapy. A common metabolic alteration feature in TME is lipid accumulation, associated with T cell exhaustion and Treg differentiation. However, the regulatory role of free fatty acids (FFA) on T cell antitumor immunity has yet to be clearly illustrated. Our study observed that palmitic acid (PA), the most abundant saturated FFA in mouse plasma, enhanced T cell exhaustion and Tregs population in TME and increased tumor growth. In contrast, oleic acid (OA), a monounsaturated FFA, rescued PA-induced T cell exhaustion, decreased Treg population, and ameliorated T cell antitumor immunity in an obese mouse model. Mechanistically, mitochondrial metabolic activity is critical in maintaining T cell function, which PA attenuated. PA-induced T cell exhaustion and Treg formation depended on CD36 and Akt/mTOR-mediated calcium signaling. The study described a new mechanism of PA-induced downregulation of antitumor immunity of T cells and the therapeutic potential behind its restoration by targeting PA.

Keywords

Antitumor immunity; OA; PA; T cells; TME.

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