IL-17C-mediated innate inflammation decreases the response to PD-1 blockade in a model of Kras-driven lung cancer

Abstract

Chronic obstructive pulmonary disease (COPD) is associated with neutrophilic lung infammation 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 afected by a coexisting COPD. The pro-infammatory cytokine interleukin-17C (IL-17C) promotes lung infammation and is present in human lung tumors. Here, we used a Krasdriven lung cancer model to examine the function of IL-17C in infammation-promoted tumor growth. Genetic ablation of Il-17c resulted in a decreased recruitment of infammatory 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 infuenzae- (NTHi) induced COPD-like lung infammation. Chronic COPD-like infammation 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 defcient 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.