Abstract
Chronic obstructive pulmonary disease (COPD) is associated with neutrophilic lung inflammation 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 affected by a coexisting COPD. The pro-inflammatory cytokine interleukin-17C (IL-17C) promotes lung inflammation and is present in human lung tumors. Here, we used a Kras-driven lung cancer model to examine the function of IL-17C in inflammation-promoted tumor growth. Genetic ablation of Il-17c resulted in a decreased recruitment of inflammatory 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 influenzae- (NTHi) induced COPD-like lung inflammation. Chronic COPD-like inflammation 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 deficient 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.
Highlights
Lung cancer is a deadly disease responsible for more than one million deaths per year worldwide
We demonstrate that the pro-inflammatory cytokine IL-17C promotes the rapid recruitment of neutrophils into the tumor microenvironment, the expression of tumor-promoting-cytokines, and tumor proliferation in the presence of Chronic obstructive pulmonary disease (COPD)-like lung inflammation
We found that chronic COPD-like inflammation results in the expression of programmed cell death-1 (PD-1) and PD-L1 in immune cells in the tumor microenvironment independent of IL-17C
Summary
Lung cancer is a deadly disease responsible for more than one million deaths per year worldwide. Preclinical studies have shown that COPD-like airway inflammation induced by aerosolized NTHi strongly increases tumor growth in Kras mouse models through the activation of Toll-like receptor (TLR) signaling, the recruitment of neutrophils into the tumor microenvironment, and inflammatory mediators (e.g. IL-17A, IL-6)[12,13,14,15,16,17]. COPD-linked inflammation likely affects the clinical response to PD-1 blockade and NSCLC patients with a coexisting COPD may qualify for the treatment with immune checkpoint inhibitor[20,23,24]. The pro-inflammatory cytokine IL-17C is expressed by non-hematopoietic cells, such as epithelial cells, regulates innate immune functions, and is present in human lung tumors and in bronchial biopsies from COPD patients[18,25,26,27,28,29]. We provide evidence that ablation of IL-17C decreases inflammation-induced tumor growth and enhances the response to anti-PD-1 antibody treatment
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