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.