PD-L1 in melanoma: facts and myths

Abstract

The use of monoclonal antibodies that block immunologic checkpoints that would otherwise mediate the adaptive immune resistance have paved the way in cancer treatment. There is evidence that blocking the PD-1/PD-L1 axis is a strategy of overriding importance in the treatment of patients with metastatic melanoma and other solid malignancies, some of which (NSCLC, colorectal cancer, renal cell cancer, head and neck cancer) were not considered to be 'immune-responsive' diseases until recently. In this perspective article, the biological and clinical relevance of PD-L1 is summarized in the context of the immune checkpoint inhibitors as a therapeutic strategy in metastatic melanoma patients.

Keywords: PD-1; PD-L1; immune checkpoint inhibitors; melanoma; predictive; prognostic.

Figure 1.. Relevant immunosuppressive mechanisms mediated by PD-1/PD-L1 axis.

CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; iTreg: Induced regulatory T cell. Modified with permission from [3].

Figure 2.. PD-L1 status and immune cell infiltrates in the context of the melanoma microenvironment.

(A) PD-L1- melanoma in absence of immune cells; (B) strong and diffuse PD-L1 immunohistochemical staining in melanoma cells in absence of immune cells; (C) PD-L1 is expressed only focally in immune cells at the periphery of tumor aggregates but the tumor is PD-L1 negative; (D) PD-L1+ melanoma cells associated with prominent immune-cell infiltrate (original magnification ×20). The exact proportion of human melanomas that can be classified into these four categories is still an open issue although rough estimates suggest the following: PD-L1+/TILs+ 35%; PD-L1-/TILs- 40%; PD-L1+/TILs- 5% and PD-L1-/TILs+ 20% [18].

Figure 3.. Potential therapeutic strategies in inflamed and noninflamed melanoma subtypes.

In melanoma with T-cell infiltrates that trigger an adaptive immune-resistant response, defining the specific mechanism of this reactive tumor protection would allow tailoring the treatment to block that particular escape mechanism. Furthermore, LAG-3 or TIM-3 expression by PD-1+ T cells may directly modulate the size of the T-cell response supporting the rational use of multiple blockade regimens to enhance CD8⁺ T-cell responses. For treatment of melanomas without T-cell infiltrates there are two different areas of research: to generate T cells (vaccines, T-cell therapy, adoptive cell transfer, β-catenin modulation?); to combine anti-PD-1 with anti-CTLA-4 antibodies in order to prime the immune response and then elicit the effector phase. Alternatively, in BRAFV600-mutated melanomas, to explore the better combination of BRAFi e MEKi with anti-PD-1 or anti-PD-L1 antibodies concomitantly or sequentially, or anti-PD-1 e anti-CTLA-4 followed by BRAFi and MEKi and vice versa. Finally combine immune-checkpoint inhibitors with VEGFR inhibitors or poly-ADP ribose polymerase inhibitors could be another option.