Tumor-associated macrophages induce PD-L1 expression in gastric cancer cells through IL-6 and TNF-ɑ signaling

• Published in: Experimental cell research Vol. 396; no. 2; p. 112315
• Main Authors: Ju, Xiaoli, Zhang, Heng, Zhou, Zidi, Chen, Miao, Wang, Qiang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.11.2020; Elsevier
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - pathology; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Infiltrated macrophages; Interleukin-6 - metabolism; Kaplan-Meier Estimate; Models, Biological; NF-kappa B - metabolism; NF-kB and STAT3; PD-1/PD-L1; Prognosis; Signal Transduction; STAT3 Transcription Factor - metabolism; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; TNF-ɑ and IL-6; Tumor Necrosis Factor-alpha - metabolism; Tumor-Associated Macrophages - metabolism; Infiltrated macrophages; TNF-ɑ and IL-6; NF-kB and STAT3; PD-1/PD-L1
• ISSN: 0014-4827; 1090-2422; 1090-2422
• DOI: 10.1016/j.yexcr.2020.112315

PD-1/PD-L1 immune checkpoint blockade therapy has been widely used for the clinical treatment of cancer. However, recent clinical trials have shown that only a small proportion of cancer patients respond to PD1/PD-L1 immunotherapy. The tumor immune microenvironment plays an important regulatory role in PD1/PD-L1 immunotherapy. Macrophages are one of the most important immune cells in the tumor immune microenvironment. In this study, we found a high correlation between macrophage infiltration and PD-L1 expression in gastric cancer (GC) specimens. Further study revealed that infiltrated macrophages released the proinflammatory cytokines TNF-ɑ and IL-6, which induced PD-L1 expression in tumor cells. The release of TNF-ɑ and IL-6 activated the NF-kB and STAT3 signaling pathway to regulate PD-L1 expression. TNF-α, p-65 and STAT3 expression in cancer patients has prognostic value in stomach adenocarcinoma. Furthermore, infiltrated macrophages can also promote GC cell proliferation by inducing PD-L1 expression in GC cells. Taken together, our results suggest that macrophages play a dual role in regulating the expression of PD-L1 in tumor cells. On the one hand, macrophages induce PD-L1 expression in tumor cells, helping tumor cells escape cytotoxic T cell killing; on the other hand, they can promote the proliferation of tumor cells by regulating the expression of PD-L1.