Chronic NTHi-Induced Inflammation Results in Activation of the PD-1 Immune Checkpoint in the Tumor Microenvironment

Microbial colonization contributes to chronic neutrophilic inflammation in COPD. Nontypeable Haemophilus influenzae (NTHi) is frequently found in lungs of stable COPD patients and is the major pathogen triggering exacerbations. Immune-checkpoint inhibitors, such as antibodies targeting the PD-1/PD-L1 axis, have demonstrated efficacy as therapeutic agents for non-small cell lung cancer. Here, we analyzed the activation of the PD-1 immune checkpoint in the tumor microenvironment of mice chronically exposed to NTHi. Mice with an oncogenic Kras allele in lung epithelium were exposed to NTHi for four weeks. The expression of PD-1 and PD-L1 was determined via immunohistochemistry and FACS analysis. Numbers of immune cells were determined in BAL fluids and via immunohistochemistry. Mice were treated with an antibody targeting PD-1 or an isotype antibody. Chronic exposure to NTHi resulted in the recruitment of neutrophils and lymphocytes into the tumor microenvironment, increased membrane expression of PD-L1 in myeloid cells and increased expression of PD-1 in CD4 and CD8 positive lymphocytes. Anti-PD-1 immunotherapy reduced neutrophilic inflammation of the lung. Chronic neutrophilic inflammation induced by NTHi activates the PD-1 immune checkpoint in the tumor microenvironment.