Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity

Yugang Guo, Yu Qing Xie, Min Gao, Yang Zhao, Fabien Franco, Mathias Wenes, Imran Siddiqui, Alessio Bevilacqua, Haiping Wang, Hanshuo Yang, Bing Feng, Xin Xie, Catherine M. Sabatel, Benjamin Tschumi, Amphun Chaiboonchoe, Yuxi Wang, Weimin Li, Weihua Xiao, Werner Held, Pedro RomeroPing Chih Ho, Li Tang

Research output: Contribution to journalArticlepeer-review


T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8+ tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10–Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8+ tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10–Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)746-756
Number of pages11
JournalNature Immunology
Issue number6
StatePublished - Jun 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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