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

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-alpha and IL-6, which induced PD-L1 expression in tumor cells. The release of TNF-alpha and IL-6 activated the NF-kB and STAT3 signaling pathway to regulate PD-L1 expression. TNF-alpha, 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.