NLRP3/Caspase-1 inflammasome activation is decreased in alveolar macrophages in patients with lung cancer

Lung cancer (LC) remains the leading cause of cancer-related mortality. The interaction of cancer cells with their microenvironment, results in tumor escape or elimination. Alveolar macrophages (AMs) play a significant role in lung immunoregulation, however their role in LC has been outshined by the study of tumor associated macrophages. Inflammasomes are key components of innate immune responses and can exert either tumor-suppressive or oncogenic functions, while their role in lung cancer is largely unknown. We thus investigated the NLRP3 pathway in Bronchoalveolar Lavage derived alveolar macrophages and peripheral blood leukocytes from patients with primary lung cancer and healthy individuals. IL-1β and IL-18 secretion was significantly higher in unstimulated peripheral blood leukocytes from LC patients, while IL-1β secretion could be further increased upon NLRP3 stimulation. In contrast, in LC AMs, we observed a different profile of IL-1β secretion, characterized mainly by the impairment of IL-1β production in NLRP3 stimulated cells. AMs also exhibited an impaired TLR4/LPS pathway as shown by the reduced induction of IL-6 and TNF-α. Our results support the hypothesis of tumour induced immunosuppression in the lung microenvironment and may provide novel targets for cancer immunotherapy.

肺癌（Lung Cancer, LC）仍是癌症相关死亡的首要病因。癌细胞与其微环境的相互作用，可导致肿瘤免疫逃逸或被清除。肺泡巨噬细胞（Alveolar Macrophages, AMs）在肺部免疫调控中发挥重要作用，但其在肺癌中的功能却被肿瘤相关巨噬细胞的相关研究所掩盖。炎症小体（Inflammasomes）是先天免疫应答的关键组成部分，既可发挥肿瘤抑制功能，也可具有致癌作用，但其在肺癌中的作用尚不明晰。因此，我们针对原发性肺癌患者与健康个体的支气管肺泡灌洗液来源肺泡巨噬细胞及外周血白细胞中的NLRP3通路展开了研究。肺癌患者未受刺激的外周血白细胞中，IL-1β与IL-18的分泌水平显著升高；而经NLRP3刺激后，IL-1β的分泌还可进一步上调。与之相反，在肺癌患者的肺泡巨噬细胞中，我们观察到IL-1β分泌模式存在显著差异，其主要特征为经NLRP3刺激后的细胞IL-1β生成受损。肺泡巨噬细胞同时还存在TLR4/LPS通路功能受损的情况，表现为IL-6与TNF-α的诱导表达水平降低。本研究结果支持肿瘤诱导肺部微环境免疫抑制的相关假说，或可为癌症免疫治疗提供全新的靶点。