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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
B7-H1 Antigen / biosynthesis
-
B7-H1 Antigen / genetics
-
CD8-Positive T-Lymphocytes / immunology
-
Carcinoma, Non-Small-Cell Lung / drug therapy*
-
Carcinoma, Non-Small-Cell Lung / etiology
-
Carcinoma, Non-Small-Cell Lung / immunology
-
Cell Line, Tumor
-
Cytokines / physiology
-
Female
-
Genes, ras
-
Humans
-
Immunity, Innate*
-
Interleukin-17 / deficiency
-
Interleukin-17 / genetics
-
Interleukin-17 / pharmacology
-
Interleukin-17 / physiology*
-
Lung Neoplasms / drug therapy*
-
Lung Neoplasms / etiology
-
Lung Neoplasms / immunology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Molecular Targeted Therapy
-
Neoplasm Proteins / antagonists & inhibitors*
-
Neoplasm Proteins / biosynthesis
-
Neoplasm Proteins / genetics
-
Neutrophils / physiology
-
Programmed Cell Death 1 Receptor / antagonists & inhibitors*
-
Programmed Cell Death 1 Receptor / biosynthesis
-
Programmed Cell Death 1 Receptor / genetics
-
Proto-Oncogene Proteins p21(ras) / physiology*
-
Pulmonary Disease, Chronic Obstructive / complications
-
Pulmonary Disease, Chronic Obstructive / immunology
-
Recombinant Proteins / pharmacology
-
Tumor Microenvironment
Substances
-
B7-H1 Antigen
-
Cd274 protein, mouse
-
Cytokines
-
IL17C protein, human
-
Il17c protein, mouse
-
Interleukin-17
-
Neoplasm Proteins
-
Pdcd1 protein, mouse
-
Programmed Cell Death 1 Receptor
-
Recombinant Proteins
-
Hras protein, mouse
-
Proto-Oncogene Proteins p21(ras)