TNF‐α‐dependent lung inflammation upregulates PD‐L1 in monocyte‐derived macrophages to contribute to lung tumorigenesis

Chronic inflammation, which is dominated by macrophage‐involved inflammatory responses, is an instigator of cancer initiation. Macrophages are the most abundant immune cells in healthy lungs, and associated with lung tumor development and promotion. PD‐L1 is a negative molecule in macrophages and correlated with an immunosuppressive function in tumor environment. Macrophages expressing PD‐L1, rather than tumor cells, exhibits a critical role in tumor growth and progression. However, whether and how PD‐L1 in macrophages contributes to inflammation‐induced lung tumorigenesis requires further elucidation. Here, we found that higher expression of PD‐L1 in CD11b+CD206+ macrophages was positively correlated with tumor progression and PD‐1+CD8+ T cells population in human adenocarcinoma patients. In the urethane‐induced inflammation‐driven lung adenocarcinoma (IDLA) mouse model, the infiltration of circulating CD11bhighF4/80+ monocyte‐derived macrophages (MoMs) was increased in pro‐tumor inflamed lung tissues and lung adenocarcinoma. PD‐L1 was mainly upregulated in MoMs associated with enhanced T cells exhaustion in lung tissues. Anti‐PD‐L1 treatment can reduce T cells exhaustion at pro‐tumor inflammatory stage, and then inhibit tumorigenesis in IDLA. The pro‐tumor lung inflammation depended on TNF‐α to upregulate PD‐L1 and CSN6 expression in MoMs, and induced cytokines production by alveolar type‐II cells (AT‐II). Furthermore, inflammatory AT‐II cells could secret TNF‐α to upregulate PD‐L1 expression in bone‐marrow driven macrophages (BM‐M0). Inhibition of CSN6 decreased PD‐L1 expression in TNF‐α‐activated macrophage in vitro, suggesting a critical role of CSN6 in PD‐L1 upregulation. Thus, pro‐tumor inflammation can depend on TNF‐α to upregulate PD‐L1 in recruited MoMs, which may be essential for lung tumorigenesis.