Myeloid cells in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is highly associated with inflammation. Myeloid cells, including tumor-associated macrophages and myeloid-derived suppressor cells, are abundant in the HCC microenvironment and are often associated with poor prognosis. Myeloid cells in HCC play a vital role in supporting tumor initiation, progression, angiogenesis, metastasis, and therapeutic resistance. Here, we summarize our current knowledge about myeloid cells in HCC and focus on their immune-suppressive activities and tumor-promoting functions, as well as the relevance to potential new therapies in HCC.

Figure 1

Classically activated M1 and alternatively activated M2 Macrophages. Macrophages originate from myeloid progenitors and circulating monocytes. Macrophages are incredibly plastic in response to various environmental stimuli, and can be in a spectrum of functional states. The two polarization states at the extreme end are the classical activation state (M1) and the alternative activation state (M2). LPS and IFNg generate classically activated M1 macrophages which has proinflammatory activities, express high HLA-DR and IL-12, and stimulate effector T cell function. IL-4, IL-10 and IL-13 generate alternatively activated M2 macrophages which produce low IL-12, high IL-10 and PD-L1 (B7-H1) and has immunosuppressive functions.

Figure 2

The immunosuppressive and tumor-promoting functions of TAMs and MDSCs in HCC. HCC TAMs and MDSCs suppress T cell effector functions through their expression of IDO, arginase, B7-H1 (PD-L1) and Galectin-9, induction and recruitment of regulatory T cells, as well as MDSC-mediated suppression of NK cells. TAMs promote HCC development and proliferation through TNFα and IL-6-activated NF-κB and C/EBPβ pathway. TAM-derived SDF-1α, VEGF and MMPs induce angiogenesis in HCC. HCC TAMs enhance CSCs through IL-6-activated STAT3 signaling. HCC TAMs are found at the invasive front of tumors and associated with invasion and metastasis. TAM-derived TGFβ induce EMT and enhance HCC metastasis. MMPs disrupt basement membrane and also facilitate tumor cell invasion. Surface markers used to identify HCC TAMs and MDSCs in mouse and human are listed in blue.