A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance

Abstract

Ten years since the immune checkpoint inhibitor ipilimumab was approved for advanced melanoma, it is time to reflect on the lessons learned regarding modulation of the immune system to treat cancer and on novel approaches to further extend the efficacy of current and emerging immunotherapies. Here, we review the studies that led to our current understanding of the melanoma immune microenvironment in humans and the mechanistic work supporting these observations. We discuss how this information is guiding more precise analyses of the mechanisms of action of immune checkpoint blockade and novel immunotherapeutic approaches. Lastly, we review emerging evidence supporting the negative impact of melanoma metabolic adaptation on anti-tumor immunity and discuss how to counteract such mechanisms for more successful use of immunotherapy.

Figure 1.. The immune microenvironment of melanoma.

a, Schematic representation of the principal immune components in the melanoma microenvironment. Four main functional modules can be distinguished: (1) a CD8 module (red/orange), including cytotoxic T cells (CTLs) and a spectrum of dysfunctional cells including progenitor Tex (pT_EX) and terminal T_EX cells; (2) an innate module (violet/purple), which impact on the recruitment and activation of T cells depending on the tolerogenic (tolerogenic DCs; myeloid derived suppressor cells, MDSC), pro- (M2) or anti-tumor (DCs) inflammatory potential; (3) a CD4 module (green), which is highly heterogeneous and can be shaped by the immune cells in the other modules and include immunosuppressive Tregs, Th2 cells with pro-tumor inflammatory potential and Tfh-like cells which can promote B cell function; and (4) a B cell module (blue), including B cells in various stages of differentiation up to plasma cells (PCs), with pro- or anti-tumor function depending on the profile of immunoglobulins produced (IgA, IgG2, IgG4 vs. IgG1 respectively) and expression of co-inhibitory molecules (e.g. IL-10 and PD-L1). Each of these immune modules has a counter-regulatory program to dampen immune responses, thus explaining the coexistence of tumor cells and anti-tumor lymphocytes in the same environment. b, The immune infiltrate in melanoma can organize in cellular aggregates defined as a tertiary lymphoid structure (TLS), with B cells at the core surrounded by T cells and APCs, which generate a germinal-center like pattern. The impact of these structures on anti-tumor immunity is likely determined by the potential to recruit or expand CTLs and Th1 cells vs. immunosuppressive or T_EX cells. Created with BioRender.com.

Figure 2.. Main cellular targets of ICB in humans.

Schematic representation of the immune cell types primarily affected by anti-CTLA-4 (red arrows) and ani-PD-1 (blue arrows) as reported in humans. Notably, most of these cell types overexpress the targets of ICB, potentially explaining their preferential modulation after ICB. CTLA-4 blockade induces Th1 effector cells (eff) and Tfh cells, while counteracting Treg function and possibly expanding Tex. PD-1 blockade reinvigorates T_EX and possibly potentiates effector CD8⁺ CTLs but expands functionally suppressive Tregs and can decrease Tfh. Combined assessment of these immune cell subsets during ICB will likely help select relevant pharmacodynamic changes that can be then taken as reliable activity biomarkers for these treatments. Dark color, definitive evidence; light color, weaker evidence. Created with BioRender.com.

Figure 3.. Impact of melanoma metabolism on the immune microenvironment and response to ICB.

Schematic representation of possible metabolic scenarios in melanoma. Left, the pro-oncogenic program of melanoma, converging on MAPK and/or PI3K-AKT activation, supports a highly glycolytic profile, which results in a glucose-deprived and lactate-enriched environment that creates a metabolic barrier to glycolytic effector immune cells (e.g. NK cells and CTLs) and preferentially retains Tregs and T_EX due to their reliance on alternative sources of fuels (e.g. lactate and fatty acids, FA). This TME potentiates Treg stability and suppressive profiles and poses specific obstacles to the activity of CTLA-4 blockade. Right, the metabolic state of melanoma can evolve with tumor progression and metastasis dissemination through the acquisition of a hypermetabolic phenotype, including the ability to sustain oxidative metabolism, such as in brain metastases. Low oxygen tension fosters the development of terminal T_EX, generating an environment that is particularly refractory to the activity of PD-1 blockade. Created with BioRender.com.