Department of Internal Medicine V - Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, 66421, Homburg, Germany.
Department of Clinical Laboratory, Shanghai Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China.
Sci Rep. 2019 Jul 17;9(1):10353. doi: 10.1038/s41598-019-46759-8.
Chronic obstructive pulmonary disease (COPD) is associated with neutrophilic lung inflammation and CD8 T cell exhaustion and is an important risk factor for the development of non-small cell lung cancer (NSCLC). The clinical response to programmed cell death-1 (PD-1) blockade in NSCLC patients is variable and likely affected by a coexisting COPD. The pro-inflammatory cytokine interleukin-17C (IL-17C) promotes lung inflammation and is present in human lung tumors. Here, we used a Kras-driven lung cancer model to examine the function of IL-17C in inflammation-promoted tumor growth. Genetic ablation of Il-17c resulted in a decreased recruitment of inflammatory cells into the tumor microenvironment, a decreased expression of tumor-promoting cytokines (e.g. interleukin-6 (IL-6)), and a reduced tumor proliferation in the presence of Haemophilus influenzae- (NTHi) induced COPD-like lung inflammation. Chronic COPD-like inflammation was associated with the expression of PD-1 in CD8 lymphocytes and the membrane expression of the programmed death ligand (PD-L1) independent of IL-17C. Tumor growth was decreased in Il-17c deficient mice but not in wildtype mice after anti-PD-1 treatment. Our results suggest that strategies targeting innate immune mechanisms, such as blocking of IL-17C, may improve the response to anti-PD-1 treatment in lung cancer patients.
慢性阻塞性肺疾病（COPD）与中性粒细胞性肺炎症和 CD8 T 细胞耗竭有关，是非小细胞肺癌（NSCLC）发展的重要危险因素。程序性细胞死亡-1（PD-1）阻断在 NSCLC 患者中的临床反应是可变的，并且可能受到共存的 COPD 的影响。促炎细胞因子白细胞介素-17C（IL-17C）促进肺炎症，并存在于人类肺肿瘤中。在这里，我们使用 Kras 驱动的肺癌模型来研究 IL-17C 在炎症促进肿瘤生长中的作用。Il-17c 的基因缺失导致炎症细胞向肿瘤微环境的募集减少，促肿瘤细胞因子（例如白细胞介素-6（IL-6））的表达减少，以及流感嗜血杆菌（NTHi）诱导的 COPD 样肺炎症存在时肿瘤增殖减少。慢性 COPD 样炎症与 CD8 淋巴细胞中 PD-1 的表达以及与 IL-17C 无关的程序性死亡配体（PD-L1）的膜表达相关。在 Il-17c 缺陷小鼠中，肿瘤生长减少，但在野生型小鼠中，抗 PD-1 治疗后肿瘤生长没有减少。我们的结果表明，靶向先天免疫机制的策略，如阻断 IL-17C，可能会改善肺癌患者对抗 PD-1 治疗的反应。
