Biological Factors behind Melanoma Response to Immune Checkpoint Inhibitors

Abstract

Modern immunotherapy together with targeted therapy has revolutionized the treatment of advanced melanoma. Inhibition of immune checkpoints significantly improved the median overall survival and gave hope to many melanoma patients. However, this treatment has three serious drawbacks: high cost, serious side effects, and an effectiveness limited only to approximately 50% of patients. Some patients do not derive any or short-term benefit from this treatment due to primary or secondary resistance. The response to immunotherapy depends on many factors that fall into three main categories: those associated with melanoma cells, those linked to a tumor and its microenvironment, and those classified as individual ontogenic and physiological features of the patient. The first category comprises expression of PD-L1 and HLA proteins on melanoma cells as well as genetic/genomic metrics such as mutational load, (de)activation of specific signaling pathways and epigenetic factors. The second category is the inflammatory status of the tumor: "hot" versus "cold" (i.e., high versus low infiltration of immune cells). The third category comprises metabolome and single nucleotide polymorphisms of specific genes. Here we present up-to-date data on those biological factors influencing melanoma response to immunotherapy with a special focus on signaling pathways regulating the complex process of anti-tumor immune response. We also discuss their potential predictive capacity.

Keywords: biomarkers of response; immune checkpoint inhibitors; immunotherapy; melanoma.

Figure 1

A nested hierarchy of biological factors influencing the anti-tumor immune response at the cell, tumor, and body levels. On a melanoma cell level, the immune response depends on such factors as tumor mutational burden (TMB), expression of the ligand of PD-1 molecule (PD-L1), and HLA proteins responsible for neoantigens presentation. On the tumor level, the anti-melanoma response is regulated by the presence of immune cells (“hot” tumors vs. “cold” tumors) and on the level of the organism by the microbiome, inherited profile of single nucleotide polymorphisms (SNPs) and status of the peripheral immune system.

Figure 2

The graphical summary of biological factors influencing anti-tumor immune response constituting three categories depending on anatomical level: tumor cell, tumor microenvironment, and the whole body. Melanoma cells influence anti-tumor response passively (through the number of mutations and neoantigens) and actively (by regulating some key signaling pathways). The unresponsive cell (right part of the schematic cell) is characterized by a low tumor mutational burden (TMB), low expression of neoantigens, HLA molecules, and PD-L1 ligand (indicated with downward arrows) as well as activated β-catenin and PI3K/AKT pathways and a suppressed IFNγ pathway (indicated with upward and downward arrows, respectively). Deregulation of these pathways results in the secretion of specific cytokines (e.g., VEGF, IL-10, TGF-β). They induce immunosuppressive topography of the immune cells within the tumor, which is characterized by a low density of the cytotoxic immune cells and the predominance of the immunosuppressive cells (Tregs, MDSC) (the right part of the schematic tumor). On the whole body level, the response of melanoma to immunotherapy is modulated by the specific gut microflora, constellation of peripheral immune cells, and inherent genetic variants of some important proteins e.g., HLA. The response of the tumor to the immune checkpoints inhibitors as well as the success of the immunotherapy depends on all those biological factors.