In melanoma the immune system plays a crucial role in both early response and subsequent resistance to MAPK/ERK-targeted therapies, including inhibitors of mutant BRAF. As such, there is compelling rationale for combining targeted therapies with immune-based therapies. We have previously shown that CDK4 inhibitors (CDK4i) synergize with BRAFi to overcome drug resistance in human xenograft melanoma models that lack an adaptive immune system. The immune-related effects of CDK4i, both alone and in combination with BRAFi and other MAPK/ERK-targeted inhibitors, are largely undefined. Recently several syngeneic melanoma models have been developed using murine melanoma cell lines with specific human-relevant genetic backgrounds (YUMM cells; Meeth et al, 2016). Using these models we will investigate the effects of CDK4 and MAPK/ERK pathway inhibitors on immune cell function and tumour immunosensitization. We hypothesize that targeting these pathways will alter the tumour microenvironment and the immune responses to melanoma. Our initial studies indicate that CDK4i and BRAFi directly alter the ability of T cells to kill YUMM cells in vitro, with distinct differences in the effects of single agents and the combination. We have also demonstrated that select YUMM models are immunogenic, expresses key immune molecules including MHC I and PD-L1, and that the various YUMM cell lines have distinct sensitivities to CDK4i, BRAFi and MEKi. Collectively these YUMM models provide complementary settings in which to study the effect of CDK4i and various MAPK/ERK-inhibitor combinations on the immune response to melanoma, and may be used to subsequently guide strategic development of combined targeted and immune-based therapy approaches to treat this malignancy.