1 Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS 1138, Cordeliers Research Center, Team Cancer, Immune Control and Escape, Paris, France.
2 Paris Descartes-Paris 5 University, Paris, France.
Am J Respir Crit Care Med. 2018 Oct 1;198(7):928-940. doi: 10.1164/rccm.201706-1110OC.
Patients with chronic obstructive pulmonary disease (COPD) have a higher prevalence of lung cancer. The chronic inflammation associated with COPD probably promotes the earliest stages of carcinogenesis. However, once tumors have progressed to malignancy, the impact of COPD on the tumor immune microenvironment remains poorly defined, and its effects on immune-checkpoint blockers' efficacy are still unknown.
To study the impact of COPD on the immune contexture of non-small cell lung cancer.
We performed in-depth immune profiling of lung tumors by immunohistochemistry and we determined its impact on patient survival (n = 435). Tumor-infiltrating T lymphocyte (TIL) exhaustion by flow cytometry (n = 50) was also investigated. The effectiveness of an anti-PD-1 (programmed cell death-1) treatment (nivolumab) was evaluated in 39 patients with advanced-stage non-small cell lung cancer. All data were analyzed according to patient COPD status.
Remarkably, COPD severity is positively correlated with the coexpression of PD-1/TIM-3 (T-cell immunoglobulin and mucin domain-containing molecule-3) by CD8 T cells. In agreement, we observed a loss of CD8 T cell-associated favorable clinical outcome in COPD patients. Interestingly, a negative prognostic value of PD-L1 (programmed cell death ligand 1) expression by tumor cells was observed only in highly CD8 T cell-infiltrated tumors of COPD patients. Finally, data obtained on 39 patients with advanced-stage non-small cell lung cancer treated by an anti-PD-1 antibody showed longer progression-free survival in COPD patients, and also that the association between the severity of smoking and the response to nivolumab was preferentially observed in COPD patients.
COPD is associated with an increased sensitivity of CD8 tumor-infiltrating T lymphocytes to immune escape mechanisms developed by tumors, thus suggesting a higher sensitivity to PD-1 blockade in patients with COPD.
慢性阻塞性肺疾病（COPD）患者肺癌的患病率更高。与 COPD 相关的慢性炎症可能促进了致癌作用的早期阶段。然而，一旦肿瘤进展为恶性肿瘤，COPD 对肿瘤免疫微环境的影响仍不清楚，其对免疫检查点抑制剂疗效的影响尚不清楚。
研究 COPD 对非小细胞肺癌免疫结构的影响。
我们通过免疫组织化学对肺肿瘤进行了深入的免疫分析，并确定了其对患者生存的影响（n=435）。还通过流式细胞术研究了肿瘤浸润性 T 淋巴细胞（TIL）衰竭（n=50）。评估了 39 名晚期非小细胞肺癌患者抗 PD-1（程序性细胞死亡蛋白-1）治疗（nivolumab）的疗效。所有数据均根据患者 COPD 状况进行分析。
值得注意的是，COPD 严重程度与 CD8 T 细胞上 PD-1/TIM-3（T 细胞免疫球蛋白和粘蛋白结构域分子-3）的共表达呈正相关。同样，我们观察到 COPD 患者中 CD8 T 细胞相关的有利临床结局丧失。有趣的是，仅在 COPD 患者中高度浸润 CD8 T 细胞的肿瘤中观察到肿瘤细胞 PD-L1（程序性死亡配体 1）表达的阴性预后价值。最后，对 39 名接受抗 PD-1 抗体治疗的晚期非小细胞肺癌患者获得的数据显示，COPD 患者的无进展生存期更长，而且吸烟严重程度与 nivolumab 反应之间的关联主要在 COPD 患者中观察到。
COPD 与肿瘤发展的免疫逃逸机制使 CD8 肿瘤浸润性 T 淋巴细胞的敏感性增加有关，因此提示 COPD 患者对 PD-1 阻断的敏感性更高。
