Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1

Macrophages (M phi) are prominent components of solid tumors and exhibit distinct phenotypes in different microenvironments. We have recently found that tumors can alter the normal developmental process of M phi to trigger transient activation of monocytes in peritumoral stroma. We showed that a fraction of monocytes/M phi in peritumoral stroma, but not in cancer nests, expresses surface PD-L1 (also termed B7-H1) molecules in tumors from patients with hepatocellular carcinoma (HCC). Monocytes activated by tumors strongly express PD-L1 proteins with kinetics similar to their activation status, and significant correlations were found between the levels of PD-L1(+) and HLA-DRhigh on tumor-infiltrating monocytes. Autocrine tumor necrosis factor. and interleukin 10 released from activated monocytes stimulated monocyte expression of PD-L1. The PD-L1(+) monocytes effectively suppressed tumor-specific T cell immunity and contributed to the growth of human tumors in vivo; the effect could be reversed by blocking PD-L1 on those monocytes. Moreover, we found that PD-L1 expression on tumor-infiltrating monocytes increased with disease progression, and the intensity of the protein was associated with high mortality and reduced survival in the HCC patients. Thus, expression of PD-L1 on activated monocytes/M phi may represent a novel mechanism that links the proinflammatory response to immune tolerance in the tumor milieu.