Pulmonary microbiota, local inflammation, and tumor progression impact immune checkpoint gene profiles in the lung microenvironment.

Emerging data indicate that the lung microbiota contribute to the initiation and progression of lung cancer. Here, we investigate a wide range of immune checkpoint genes (ICGs) in the pulmonary microenvironment across lung carcinogenesis and explore the interplay between these immunoregulatory genes, the intratumoral microbiota, and inflammatory processes in the lungs. First, we establish that ICGs can considerably impact host immunity and efficacy of immunotherapy. Second, we identify CD160, HLA-DOA, and VTCN1 to significantly downregulate as tumors progress from early-stage to advanced-stage. In addition, the expression of CD86, HLA-DPB1, and HAVCR2 are significantly positively correlated with pulmonary inflammation. Finally, HLA-A, HLA-B, and HLA-E levels positively correlate to immune- and inflammation-associated Lachnoclostridium dominance. Taken together, our study uncovers ICG signatures linked to tumor progression and sheds light on the complex network of microbiota-host immunity interactions within the lung microenvironment. This study lays the groundwork for future mechanistic studies and underscores the significance of microbiota-host immunity interactions for predicting and tracking the response to cancer treatment.NEW & NOTEWORTHY This study uncovers a dynamic link between the evolving lung microbiota and the expression of specific immune checkpoint genes during cancer progression. We identify key genes that correlate with tumor advancement or inflammation and, notably, reveal a novel positive association between HLA molecules and a proinflammatory bacterial genus. These findings illuminate the microbiota-immune interplay in the lung tumor microenvironment, offering new potential targets and biomarkers for therapy.