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

FASEB J. 2022 Nov;36(11):e22595. doi: 10.1096/fj.202200434RR.

Abstract

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 CD11bhigh F4/80+ 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.

Keywords: Monocyte-derived macrophages; PD-L1; TNF-α; chronic inflammation; lung tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung* / metabolism
  • Adenocarcinoma* / pathology
  • Animals
  • B7-H1 Antigen
  • CD8-Positive T-Lymphocytes / metabolism
  • Carcinogenesis / pathology
  • Cell Transformation, Neoplastic / metabolism
  • Humans
  • Inflammation / metabolism
  • Lung / metabolism
  • Lung Neoplasms* / metabolism
  • Macrophages / metabolism
  • Mice
  • Pneumonia* / metabolism
  • Programmed Cell Death 1 Receptor / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Urethane / metabolism

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Programmed Cell Death 1 Receptor
  • Tumor Necrosis Factor-alpha
  • Urethane