Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

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.

Treatment of Advanced Melanoma: Past, Present and Future

“…In another report, Irimada et al found a correlation between serum CXCL5 levels and onset of rhabdomyolysis caused by D + T therapy [43]. Since all of these soluble factors described above are well-known TAM-related factors [46], BRAF/MEK inhibitors might activate TAMs in advanced melanoma patients directly or indirectly, leading to production of these soluble factors and development of characteristic AEs.…”

The Role of Tumor Microenvironment in Mycosis Fungoides and Sézary Syndrome

“…Recent report suggested PD-1-PD-L1 therapies may also function through a direct effect on TAMs, and when PD-L1/PD-1 signaling is blocked by antibodies, CD163+ TAMs activated and polarized into M1-like TAMs 68 . Since the profiles of chemokines are different between M1 and M2 polarized macrophages, M1-polarized macrophages not only induce cytotoxic reaction against lymphoma cells, but also work together with other immunosuppressive cells 69 .…”

Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

“…On the other hand, TAMs are involved in cancer progression through the release of specific protumoral cytokines such as interleukin IL-6, IL-8 and IL-10 [ 37 , 38 , 39 , 40 ]. TAMs are also able to express immune checkpoint modulators such as PD-L1 and various chemokines (C-C motif chemokine ligand 17 (CCL17), CCL22, C-X-C motif chemokine ligand 10 (CXCL10)) which attract effector/activated T regs that exert an immunosuppressive action and promote tumor growth ( Figure 1 C) [ 36 , 37 , 38 , 41 , 42 , 43 ].…”