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.
Cell reports. 2023 Nov 13 [Epub ahead of print]
Fan Xu, Xiumei Wang, Ying Huang, Xiaoqian Zhang, Wenbo Sun, Yuanyuan Du, Zhi Xu, Hengyuan Kou, Shuyi Zhu, Caidong Liu, Xiaowei Wei, Xiao Li, Qin Jiang, Yong Xu
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., 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., 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., 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., Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, 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: ., Research Center, Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, P.R. China. Electronic address: ., 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: .