Cancer immunoediting by melanocyte differentiation antigen-specific T cells determines response to immune checkpoint inhibition

Abstract T cells are critical in cancer immune surveillance but they can also shape tumor immunogenicity, described as cancer immunoediting. Melanoma patients commonly harbor T cells recognizing melanocyte differentiation antigens (MDAs). However, the roles of MDA-specific T cells in shaping melanoma immunogenicity and the response to immune checkpoint inhibition remain elusive. Here, we prospectively profiled peripheral CD8+ T cells from 27 stage IV patients before initiation of checkpoint inhibitor therapy. Clinical failure was associated with increased MDA-specific CD8+ T cells and reduced tumor MDA expression pretreatment. In nonresponders, decreased tumor MDA expression was concomitant with a dedifferentiated melanoma phenotype. We confirmed in 30 stage III patients that individuals with relapse disease during adjuvant anti-PD-1 therapy demonstrated a significantly higher incidence of dedifferentiated tumors pretreatment than individuals without recurrence. Thus, MDA-directed CD8+ T cells are associated with a dedifferentiated phenotype and reduced clinical response to checkpoint inhibitor therapy suggesting immunoediting as an important resistance mechanism.