Impaired Tumor-Infiltrating T Cells in Patients with Chronic Obstructive Pulmonary Disease Impact Lung Cancer Response to PD-1 Blockade

Abstract

Rationale: 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.

Objectives: To study the impact of COPD on the immune contexture of non-small cell lung cancer.

Methods: 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.

Measurements and main results: 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.

Conclusions: 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.

Keywords: CD8 tumor-infiltrating T lymphocytes; anti–PD-1; non–small cell lung cancer; tumor immunology.