Zhou Yan, Hu Zhangguo, Cao Shuhui, Yan Bo, Qian Jialin, Zhong Hua
Department of Pulmonary Disease, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
Department of Respiration Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
Oncol Rep. 2017 Aug;38(2):685-692. doi: 10.3892/or.2017.5733. Epub 2017 Jun 19.
Lung cancer is the most common malignancy in humans. An increased population of CD4+Foxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. The exact role and the involved mechanisms of concomitant H37Rv infection in non-small cell lung cancer (NSCLC) development are still not clear. Here, we showed that H37Rv infection promoted NSCLC cell growth with a higher percentage of Tregs found in draining lymph nodes. We also determined in vitro that H37Rv infection induced macrophage maturation and PD-L1 expression, which promoted Treg proportion, with enhanced proliferation suppression function. Mechanism analysis revealed that AKT-mTORC1 signal was important for PD-L1 expression induced by H37Rv infection. Suppressing of AKT-mTORC1 signal by rapamycin or raptor deficiency showed decreased PD-L1 levels which further reduced Treg proportion in a co-culture system. Finally, tumor-bearing mice injected with H37Rv plus rapamycin enhance the immune response of lung cancer compared with injected with H37Rv alone. This study demonstrated that concomitant H37Rv infection promote NSCLC tumor immune eacape through enhancing Treg proportion.
肺癌是人类最常见的恶性肿瘤。肿瘤相关微环境中CD4+Foxp3+调节性T细胞（Tregs）数量增加在癌症免疫逃逸中起重要作用。H37Rv感染在非小细胞肺癌（NSCLC）发展中的确切作用及相关机制仍不清楚。在此，我们表明H37Rv感染促进NSCLC细胞生长，且在引流淋巴结中发现更高比例的Tregs。我们还在体外确定H37Rv感染诱导巨噬细胞成熟和PD-L1表达，这促进了Treg比例，增强了增殖抑制功能。机制分析显示AKT-mTORC1信号对H37Rv感染诱导的PD-L1表达很重要。用雷帕霉素或猛禽蛋白缺乏抑制AKT-mTORC1信号显示PD-L1水平降低，这在共培养系统中进一步降低了Treg比例。最后，与单独注射H37Rv相比，注射H37Rv加雷帕霉素的荷瘤小鼠增强了肺癌的免疫反应。本研究表明，伴随H37Rv感染通过增加Treg比例促进NSCLC肿瘤免疫逃逸。
