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  2. Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8+ T cell

Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8+ T cell

  • Cell Rep. 2023 Nov 13;42(11):113424. doi: 10.1016/j.celrep.2023.113424.
Fan Xu 1 Xiumei Wang 2 Ying Huang 3 Xiaoqian Zhang 3 Wenbo Sun 4 Yuanyuan Du 4 Zhi Xu 3 Hengyuan Kou 5 Shuyi Zhu 5 Caidong Liu 6 Xiaowei Wei 6 Xiao Li 7 Qin Jiang 8 Yong Xu 9
Affiliations

Affiliations

  • 1 Research Center, Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, P.R. China; Laboratory of Cancer Biology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting Road, Nanjing 210009, P.R. China.
  • 2 Research Center, Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, P.R. China; Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, P.R. China.
  • 3 Research Center, Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, P.R. China.
  • 4 Laboratory of Cancer Biology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting Road, Nanjing 210009, P.R. China.
  • 5 Research Center, Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, P.R. China; Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P.R. China.
  • 6 Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, P.R. China.
  • 7 Laboratory of Cancer Biology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting Road, Nanjing 210009, P.R. China. Electronic address: lixiao@njmu.edu.cn.
  • 8 Research Center, Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, P.R. China. Electronic address: jqin710@vip.sina.com.
  • 9 Research Center, Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, P.R. China; Laboratory of Cancer Biology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting Road, Nanjing 210009, P.R. China. Electronic address: yxu4696@njmu.edu.cn.
Abstract

Depletion of CD8+ T cells is a major obstacle in immunotherapy; however, the relevant mechanisms remain largely unknown. Here, we showed that prostate Cancer (PCa) cell-derived exosomes hamper CD8+ T cell function by transporting interleukin-8 (IL-8). Compared to the low IL-8 levels detected in immune cells, PCa cells secreted the abundance of IL-8 and further accumulated in exosomes. The delivery of PCa cell-derived exosomes into CD8+ T cells exhausted the cells through enhanced starvation. Mechanistically, exosomal IL-8 overactivated PPARα in recipient cells, thereby decreasing glucose utilization by downregulating GLUT1 and HK2 but increasing fatty acid catabolism via upregulation of CPT1A and ACOX1. PPARα further activates uncoupling protein 1 (UCP1), leading to fatty acid catabolism for thermogenesis rather than ATP synthesis. Consequently, inhibition of PPARα and UCP1 restores CD8+ T cell proliferation by counteracting the effect of exosomal IL-8. This study revealed that the tumor exosome-activated IL-8-PPARα-UCP1 axis harms tumor-infiltrating CD8+ T cells by interfering with energy metabolism.

Keywords

CD8(+) T cell; CP: Cancer; CP: Immunology; PPARα; exosome; glucolipid metabolism; interleukin-8; prostate cancer.

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