Mechanisms Regulating Immune Checkpoint Inhibitor PD-L2 Expression in Melanoma

Immune checkpoint inhibitors that target the programmed cell death receptor-1 (PD1) have significantly improved the survival of patients with advanced melanoma. Signalling through the PD1 receptor upon binding to its cognate ligands PD-L1 and PD-L2 suppresses T cell activity and dampens anti-tumour immune responses. Both PD-L1 and PD-L2 are expressed on melanoma cells, and this contributes to tumour evasion from the immune system. The regulation of PD-L1 expression in melanoma is well described, but much less is known about the mechanisms regulating PD-L2 expression. Interestingly, PD-L2 is highly expressed in dedifferentiated melanomas, a phenotypic subset of melanoma cells highly resistant to immune checkpoint inhibitors. In this thesis, we investigated the expression of PD-L2, at the transcript and protein level, in a small panel of melanoma cell lines with distinct differentiation status. We explored the effects of cytokine exposure, hypomethylation and oncogenic pathway inhibition on PD-L2 expression in melanoma. We show that the cytokines TNFα and IFNγ induce PD-L2 expression in both melanocytic and dedifferentiated melanoma phenotypes. However, basal expression of PD-L2 is cell-type specific and partially dependent on tumour-intrinsic Src and FAK signalling. Our results indicate that PD-L2 is regulated independently of PD-L1, and differences in response to cytokine induction, the epigenetic methylation status, and constitutive oncogenic pathway signalling may reflect basal differences in PD-L2 expression between distinct melanoma phenotypes.