Elucidating Mechanisms of T cell Exclusion in Melanoma

Abstract

Advanced melanoma was an almost incurable disease in the early 2010s. Today, about half of patients can achieve durable clinical responses with new targeted therapies, including immune checkpoint blockade therapies. The immune composition of the tumor microenvironment (TME) substantively impacts immunotherapy responses. Tumor-infiltrating T lymphocytes are known to play a particularly beneficial role, but the underlying mechanisms that allow or block T cell infiltration are incompletely understood. In my analyses, I implanted five human melanoma cell lines into humanized MISTRG mice and found that they recapitulate the characteristic types of immune cell infiltration patterns seen in patients; i.e., T cell infiltrated (‘hot’) versus T cell excluded/desert (‘cold’). These T cell infiltration patterns were not associated with T cell antigen specificity or macrophage abundance. My colleagues and I identified unique transcriptional signatures for the hot vs. cold melanoma cell lines. I validated these signatures in publicly available data from 48 patient-derived melanoma cell lines, and showed that the signatures predicted in vivo T cell infiltration versus exclusion for eight representative cell lines. We next found that melanoma cell differentiation stages tightly correlated with the T cell infiltration/ exclusion signatures, where less differentiated melanomas had more T cell infiltration and more differentiated melanomas excluded T cells from the TME. Of note, patients with less differentiated tumors have longer overall survival. Ongoing analyses aim to identify actionable molecular targets within the hot versus cold signatures. Long-term, these findings can inform the design of novel therapeutic strategies, which may have applications across diverse human tumor types and improve outcomes for many patients.