Stromal Factors as a Target for Immunotherapy in Melanoma and Non-Melanoma Skin Cancers

Abstract

Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death 1 (PD1) antibodies (Abs) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) Abs, have been widely administered for not only advanced melanoma, but also various non-melanoma skin cancers. Since profiles of tumor-infiltrating leukocytes (TILs) play important roles in immunotherapy using ICIs, it is important to evaluate cancer stromal cells such as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), as well as stromal extracellular matrix protein, to predict the efficacy of ICIs. This review article focuses particularly on TAMs and related factors. Among TILs, TAMs and their related factors could be the optimal biomarkers for immunotherapy such as anti-PD1 Ab therapy. According to the studies presented, TAM-targeting therapies for advanced melanoma and non-melanoma skin cancer will develop in the future.

LL-37 Might Promote Local Invasion of Melanoma by Activating Melanoma Cells and Tumor-Associated Macrophages

“…Notably, MMP-9 inhibition blocked formation of pillars in vessels, and the inhibition of MMP-9 promotes abrogated pillar formation in melanoma [ 39 ], leading to suppression of angiogenesis in melanomas. TAMs also produce various MMPs, which play critical roles in the tissue remodeling associated with protein cleavage to modify the immune microenvironment, angiogenesis, tissue repair, local invasion, and metastasis [ 40 ]. Notably, MMPs are among the central angiogenetic factors associated with M2-polarized TAMs in skin cancers [ 40 ].…”

“…TAMs also produce various MMPs, which play critical roles in the tissue remodeling associated with protein cleavage to modify the immune microenvironment, angiogenesis, tissue repair, local invasion, and metastasis [ 40 ]. Notably, MMPs are among the central angiogenetic factors associated with M2-polarized TAMs in skin cancers [ 40 ]. For example, osteopontin signaling increased the secretion of MMP-9 from TAMs to promote angiogenesis and tumor progression in a melanoma model [ 41 ].…”

Chemokines as possible therapeutic targets in metastatic melanoma

“…Furthermore, in many skin cancers, including melanoma, TAMs may directly produce immunosuppressive chemokines, 31 which may attract other immunosuppressive cells, including MDSCs, Tregs and TANs. 37 MDSCs and TANs suppress T cells and NK cells and recruit Treg cells, which suppress T cell responses and promote cancer immune evasion and escape. 34,35 However, the crosstalk between signalling pathways and immune responses presents a complex and dynamic system in the context of cancer development and progression within the tumour microenvironment.…”

“…In contrast, pro‐tumour effector cells include tumour‐associated macrophages (TAMs), myeloid‐derived suppressor cells (MDSC), tumour‐associated neutrophils (TANs) and regulatory T cells (Treg) 37 . TAMs are found in cutaneous melanoma and in several non‐melanoma skin cancers 37 .…”

A CD8+ T cell-associated immune gene panel for prediction of the prognosis and immunotherapeutic effect of melanoma

“…In particular, on the condition of the approval of the use of CTLA-4 , PD-L1 , and PD-1 -specific immune checkpoint inhibitors, immunotherapy performs better than conventional therapies in lengthening the overall survival (OS) of cases of heterogeneous tumors ( 6 – 9 ). SKCM is a class of tumor displaying the most sensitive to immunotherapeutic methods ( 10 , 11 ). According to the latest clinical study, after SKCM patients underwent nivolumab + ipilimumab combination therapy, the 5-year OS rate was 52% ( 12 ).…”