Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer
Meng Qiao, Fei Zhou, Xinyu Liu, Tao Jiang, Haowei Wang, Yijun Jia, Xuefei Li, Chao Zhao, Lei Cheng, Xiaoxia Chen, Shengxiang Ren, Hongcheng Liu, Caicun Zhou
Abstract
Background Anti-PD-1(L1) therapies are less efficacious in patients with EGFR -mutated non-small-cell lung cancer. However, the underlying mechanism is poorly understood. Methods The characteristics of T cells in EGFR -mutated and wild-type tumors were analyzed based on The Cancer Genome Atlas database and clinical samples. Plasma levels of 8 T-cell-related cytokines were evaluated and its association with immunotherapy efficacy were explored. Association between EGFR signaling pathway and IL-10 was examined through tumor cell lines and clinical tumor samples. In vitro restimulation model of human CD8 + T cells isolated from peripheral blood was used to analyze the impact of IL-10 on T cells. Doxycycline-inducible transgenic EGFR L858R mouse models were used to investigate the efficacy of combining recombinant mouse IL-10 protein and PD-1 blockade and its underlying mechanism in vivo . Results EGFR -mutated tumors showed a lack of CD8 + T cell infiltration and impaired CD8 + T cell cytotoxic function. The incompetent CD8 + T cells in EGFR -mutated tumors were characterized as absence of CD39 expression, which defined hallmarks of cytotoxic and exhausted features and could not be reinvigorated by anti-PD-1(L1) treatment. Instead, CD39 expression defined functional states of CD8 + T cells and was associated with the therapeutic response of anti-PD-1(L1) therapies. Mechanically, IL-10 upregulated CD39 expression and was limited in EGFR -mutated tumors. IL-10 induced hallmarks of CD8 + T cells immunity in CD39-dependent manner. Using autochthonous EGFR L858R -driven lung cancer mouse models, combining recombinant mouse IL-10 protein and PD-1 blockade optimized antitumor effects in EGFR -mutated lung tumors. Conclusions Our study suggested that owing to low level of IL-10 to induce the expression of CD39 on CD8 + T cells, fewer phenotypically cytotoxic and exhausted CD39 + CD8 + T cells in EGFR -mutated tumors could be potentially reinvigorated by anti-PD-1(L1) treatment. Hence, IL-10 could potentially serve as a cytokine-based strategy to enhance efficacy of anti-PD-1(L1) treatment in EGFR -mutated tumors.