Targeting tumor-associated macrophages in hepatocellular carcinoma: biology, strategy, and immunotherapy

Abstract

Hepatocellular carcinoma (HCC), one of the most malignant tumors, is characterized by its stubborn immunosuppressive microenvironment. As one of the main members of the tumor microenvironment (TME) of HCC, tumor-associated macrophages (TAMs) play a critical role in its occurrence and development, including stimulating angiogenesis, enhancing immunosuppression, and promoting the drug resistance and cancer metastasis. This review describes the origin as well as phenotypic heterogeneity of TAMs and their potential effects on the occurrence and development of HCC and also discusses about various adjuvant therapy based strategies that can be used for targeting TAMs. In addition, we have highlighted different treatment modalities for TAMs based on immunotherapy, including small molecular inhibitors, immune checkpoint inhibitors, antibodies, tumor vaccines, adoptive cellular immunotherapy, and nanocarriers for drug delivery, to explore novel combination therapies and provide feasible therapeutic options for clinically improving the prognosis and quality of life of HCC patients.

Fig. 1. There are three major sources of TAMs in HCC: yolk sac, fetal liver, and bone marrow, as well as three direct sources: blood/bone marrow-derived monocytes, KCs, and MDSCs.

YFP⁺ AA4.1⁺ Kit⁺ CD45^lo EMPs (erythro-myeloid progenitor), which appeared initially in the yolk sac of a mouse embryo at E(day)8.5, have been identified as macrophage progenitor cells [135]. EMPs, which can exist as Kit⁺ progenitor cells can effectively migrate and proliferate in the fetal liver until E16.5 and produce the fetal liver monocytes (appearing at E12.5) until the late stage of fetal development [135]. Moreover, EMPs have been found to rapidly differentiate into premacrophages (pMacs), which can simultaneously colonize the whole embryo from E9.5 in a CX3CR1-dependent manner and differentiated into macrophages [136]. It has been reported that starting from E10.5, almost immediately after embryonic tissue colonization, YFP⁺F4/80^bright fetal macrophages can appear in the fetal liver [135, 136]. Thereafter, around E14.5, fetal liver monocytes can replace early F4/80^hi macrophages and constitute most of the liver-resident macrophages in the adult liver, that is, Kupffer cells (KCs) [135, 137]. During the postnatal bone formation, the hematopoietic function of the fetal liver decreases significantly and is replaced by BM [135, 138, 139]. BM-derived mononuclear phagocyte precursor MDPs (macrophage/dendritic cell progenitor cells) which can produce inflammatory monocytes (Ly6c⁺), giving rise to the patrol monocytes (Ly6c⁻) [138, 139]. Interestingly, both inflammatory monocytes (Ly6c⁺) and patrol monocytes (Ly6c^-) can be recruited into the liver capsule and then differentiate into CD207-EGFP^hi F4/80⁺ liver capsular macrophages (LCMs) [140, 141]. Inflammatory monocytes (Ly6c⁺) enter the liver and participate in the formation of the resident macrophages in a very small proportion of the tissues, namely, monocyte-derived liver macrophages (MoMFs) [31, 135, 139]. Both KCs and blood-recruited MoMFs have been found to be involved in the formation of the tumor-associated macrophages, but it is not clear whether LCMs are also involved [18, 19]. LCMs have been also rarely considered as a predecessor of TAMs because of their special anatomical location [140]. In addition, MDSCs can differentiate into immunosuppressive TAMs in the microenvironment of HCC in the presence of HIF-1α or hypoxia [142, 143]. Collectively, the precise origins of TAMs have not been fully elucidated.

Fig. 2. Reducing infiltration, inducing polarization, and inhibiting the tumor-promoting function have emerged as the main strategies for targeting TAMs in HCC.

Thus combination of any two or more approaches between small molecular drugs, immune checkpoint inhibitors, antibodies, tumor vaccines, adoptive cellular immunotherapy, nanocarriers for drug delivery (including but not limited to) might be able to achieve effective tumor inhibition or even tumor elimination.