Abstract
Tumor-associated macrophages (TAMs) have been detected in most skin cancers. TAMs produce various chemokines and angiogenic factors that promote tumor development, along with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated neutrophils. TAMs generated from monocytes develop into functional, fully activated macrophages, and TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment. Since TAMs express PD1 to maintain the immunosuppressive M2 phenotype by PD1/PD-L1 signaling from tumor cells, and the blockade of PD1/PD-L1 signaling by anti-PD1 antibodies (Abs) activate and re-polarize TAMs into immunoreactive M1 phenotypes, TAMs represent a potential target for anti-PD1 Abs. The main population of TAMs comprises CD163+ M2 macrophages, and CD163+ TAMs release soluble (s)CD163 and several proinflammatory chemokines (CXCL5, CXCL10, CCL19, etc.) as a result of TAM activation to induce an immunosuppressive tumor microenvironment together with other immunosuppressive cells. Since direct blockade of PD1/PD-L1 signaling between tumor cells and tumor-infiltrating T cells (both effector T cells and Tregs) is mandatory for inducing an anti-immune response by anti-PD1 Abs, anti-PD1 Abs need to reach the tumor microenvironment to induce anti-immune responses in the tumor-bearing host. Taken together, TAM-related factors could offer a biomarker for anti-PD1 Ab-based immunotherapy. Understanding the crosstalk between TAMs and immunosuppressive cells is important for optimizing PD1 Ab-based immunotherapy.
Highlights
Tumor-associated macrophages (TAMs) have been detected in most skin cancers [1]
TAMs express PD1, which is necessary for maintaining M2 phenotypes in TAMs via PD-L1/PD1 signaling from tumor cells [4]
Increased microRNAs in the plasma of melanoma patients are associated with the generation of myeloid-derived suppressor cells (MDSCs) mediated by melanoma extracellular vesicles, and are even associated with resistance to treatment with immune checkpoint inhibitors (ICIs) in melanoma patients [29], suggesting that MDSC-related miRs could offer a biomarker of poor prognosis in melanoma patients treated with ICIs
Summary
Tumor-associated macrophages (TAMs) have been detected in most skin cancers [1]. TAMs produce various chemokines that attract other immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated neutrophils (TANs) to maintain an immunosuppressive tumor microenvironment [1]. TAMs, and other immunosuppressive cells such as MDSCs, Tregs and TANs, should be taken into account when evaluating the immunosuppressive microenvironment of skin cancers [5,6,7]. Environmental risk factors for skin cancer (e.g., sun exposure, chemical exposure) have been widely reported [8] These risk factors modulate the profiles of tumor-infiltrating leukocytes (TILs), at least in part, through aryl hydrocarbon receptor (AhR)-dependent signal pathways [9]. Anti-PD1 Abs could abrogate the immune suppression and re-activate CD8+ cytotoxic T cells [5], and activate TAMs to induce an anti-tumor immune response by blocking of PD-L1/PD1 signaling pathway. This review discusses the differentiation, activation and immunosuppressive functions of TAMs, MDSCs, Tregs and TANs, and their benefits in cancer immunotherapy
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