Abstract

Melanoma is the deadliest form of skin cancer with 96,610 new cases and 7,990 deaths estimated for 2023 in the United States. Despite significant progress with immune-checkpoint inhibitors (ICI) targeting PD-1 and CTLA-4, many patients with advanced melanoma do not have a durable response to ICI and are at high risk for recurrence and death. Lack of a durable response is linked to failure of T-cell memory formation. However, there are currently no validated markers to identify patients predisposed to impaired memory T-cell formation and poor response to ICI. CD127 is a cell-surface cytokine receptor that regulates T-cell survival and memory differentiation. We investigated pre-treatment biopsies of 43 melanoma patients and found that CD127 hypomethylation was associated with a four-fold prolongation (p<0.05, Log-rank test) of response to ICI and could differentiate between responders and non-responders to therapy (HR=3.1). We measured CD127 expression by immunohistochemistry in a separate cohort of melanoma patients and found that high CD127 protein expression was associated with significantly longer progression free survival (HR= 8.2, p<0.01, Log-rank test) and response to ICI therapy (p<0.01, Chi-squared test). In agreement with these findings, the cytokine binding CD127 was increased in patients with durable response to ICI (p<0.05, Student’s t-test). In this pilot study using pre-treatment biopsies from independent melanoma cohorts, we report that CD127 is associated with a favorable response to immune-checkpoint therapy. A marker of immune-checkpoint therapy response could help improve care for melanoma patients by informing the provision of optimal therapies and minimizing side-effects.