Intertumoral Genetic Heterogeneity Generates Distinct Tumor Microenvironments in a Novel Murine Synchronous Melanoma Model

Synchronous metastatic melanoma, clinically defined as multiple lesions diagnosed within 6 months, has a poor prognosis. Despite recent advances in systemic immunotherapy, a majority of patients fail to respond or exhibit lesion-specific responses. While intertumoral heterogeneity has been clinically associated with lesion-specific therapeutic responses, no clear mechanism has been identified, largely due to the scarcity of preclinical models. We developed a novel murine synchronous melanoma model that recapitulates clinical intertumoral heterogeneity. We show that genetic differences between tumors generate distinct tumor immune microenvironments (TIME). These TIMEs can independently upregulate PD-1/PD-L1 expression in response to ongoing anti-tumor immunity and the presence of interferon-gamma. The simultaneous presence of multiple tumors can additionally alter the TIME of each tumor. As such, our model provides a unique approach to investigate the effects of intertumoral heterogeneity on mechanisms of immunotherapy resistance.