Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
Department of Medical Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
J Immunother Cancer. 2022 Dec;10(12). doi: 10.1136/jitc-2022-005436.
Anti-PD-1(L1) therapies are less efficacious in patients with -mutated non-small-cell lung cancer. However, the underlying mechanism is poorly understood.
The characteristics of T cells in -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. restimulation model of human CD8T cells isolated from peripheral blood was used to analyze the impact of IL-10 on T cells. Doxycycline-inducible transgenic mouse models were used to investigate the efficacy of combining recombinant mouse IL-10 protein and PD-1 blockade and its underlying mechanism .
-mutated tumors showed a lack of CD8T cell infiltration and impaired CD8T cell cytotoxic function. The incompetent CD8T cells in -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 CD8T cells and was associated with the therapeutic response of anti-PD-1(L1) therapies. Mechanically, IL-10 upregulated CD39 expression and was limited in -mutated tumors. IL-10 induced hallmarks of CD8T cells immunity in CD39-dependent manner. Using autochthonous -driven lung cancer mouse models, combining recombinant mouse IL-10 protein and PD-1 blockade optimized antitumor effects in -mutated lung tumors.
Our study suggested that owing to low level of IL-10 to induce the expression of CD39 on CD8T cells, fewer phenotypically cytotoxic and exhausted CD39CD8T cells in -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 -mutated tumors.
抗 PD-1（L1）治疗在 -突变的非小细胞肺癌患者中的疗效较差。然而，其潜在机制尚不清楚。
基于癌症基因组图谱数据库和临床样本分析了 -突变和野生型肿瘤中 T 细胞的特征。评估了 8 种 T 细胞相关细胞因子的血浆水平，并探讨了其与免疫治疗疗效的关系。通过肿瘤细胞系和临床肿瘤样本研究了 EGFR 信号通路与 IL-10 的关系。使用从外周血分离的人 CD8T 细胞的再刺激模型分析了 IL-10 对 T 细胞的影响。使用可诱导表达的转基因小鼠模型研究了联合使用重组鼠 IL-10 蛋白和 PD-1 阻断及其潜在机制的疗效。
-突变肿瘤表现出 CD8T 细胞浸润缺乏和 CD8T 细胞细胞毒性功能受损。-突变肿瘤中功能失调的 CD8T 细胞表现为缺乏 CD39 表达，这定义了细胞毒性和耗竭特征的标志，不能通过抗 PD-1（L1）治疗再激活。相反，CD39 表达定义了 CD8T 细胞的功能状态，并与抗 PD-1（L1）治疗的疗效相关。在机制上，IL-10 上调 CD39 表达，并且在 -突变肿瘤中受到限制。IL-10 以 CD39 依赖的方式诱导 CD8T 细胞免疫的特征。使用自发的 -驱动的肺癌小鼠模型，联合使用重组鼠 IL-10 蛋白和 PD-1 阻断优化了 -突变肺肿瘤的抗肿瘤效果。
我们的研究表明，由于低水平的 IL-10 诱导 CD8T 细胞上 CD39 的表达，-突变肿瘤中表型上细胞毒性和耗竭的 CD39CD8T 细胞较少，可能通过抗 PD-1（L1）治疗得到再激活。因此，IL-10 可能作为一种细胞因子策略，增强 -突变肿瘤中抗 PD-1（L1）治疗的疗效。
