Targeting inflamed and non-inflamed melanomas: biological background and clinical challenges

Immune checkpoint inhibitors (ICIs) have demonstrated impressive antitumor activity in patients with advanced and early stage melanoma, thus improving long-term survival outcomes. However, most patients derive limited benefit from immunotherapy, due to the development of primary, adaptive, or acquired resistance mechanisms. Immunotherapy resistance is a complex phenomenon that depends on genetic and epigenetic mechanisms which, in turn, drive the interplay between cancer cells and the tumor microenvironment (TME). Immunologically "cold" (i.e. non-inflamed) tumors lack or have few tumor infiltrating lymphocytes (TILs) as a result of low tumor mutational burden (TMB), defective antigen presentation, or physical barriers to lymphocyte migration, resulting in a minimal benefit from immunotherapy. In contrast, in most cases immunologically "hot" (i.e. inflamed) tumors display high TMB, implying a higher load of neoantigens and increased programmed cell death ligand 1 (PD-L1) expression, with a consequently higher rate of TILs. However, the presence of TILs does not necessarily denote the tumor as immunologically "hot", since the presence of tumor-specific CD8⁺ T cells persistently exposed to antigenic stimulation induces a dysfunctional state called "exhaustion", which leads to a reduced response to immunotherapy. In recent years, efforts have been made to characterize mechanisms of resistance to immunotherapy, and to investigate strategies to overcome treatment resistance. Indeed, predictors of response and toxicity to immunotherapy are still lacking and, to date, there are no reliable predictive biomarkers to select patients according to baseline clinical, histological, or genomic characteristics. In this review, we will focus on the morphologic and immunohistochemical characteristics of the TME, and on the molecular determinants of resistance to immunotherapy, differentiating between inflamed and non-inflamed melanomas. Then, we will provide a thorough overview of preclinical data on genetic and epigenetic mechanisms with a potential impact on the immune response and patient outcome. Finally, we will focus our attention on the role of potential biomarkers in determining disease response to immunotherapy, in the adjuvant and metastatic setting, providing an insight into current and future research in this field.