Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy

TLDR

Cancer immunotherapies improve survival for responders, yet many patients do not benefit, and activated T‑cell signatures are key determinants of response to anti‑PD‑1–based therapies. The study aims to elucidate the biological mechanisms underlying response and resistance to anti‑PD‑1 therapies to guide drug selection. The authors profiled transcriptomes and immune phenotypes of 158 melanoma tumor biopsies from patients receiving anti‑PD‑1 monotherapy or combined anti‑PD‑1/anti‑CTLA‑4 therapy. Activated T cell signatures and an EOMES+CD69+CD45RO+ effector memory T‑cell phenotype were enriched in responders, with this phenotype correlating with longer progression‑free survival and greater tumor shrinkage, especially in combined therapy.

Abstract

Highlights•Activated T cell signatures/populations drive response to anti-PD-1-based therapies•EOMES+CD69+CD45RO+ effector memory T cells are associated with response•EOMES+CD69+CD45RO+ expression is associated with longer PFS and tumor shrinkage•Non-responders with TIL-hot tumors express other immune drug targetsSummaryCancer immunotherapies provide survival benefits in responding patients, but many patients fail to respond. Identifying the biology of treatment response and resistance are a priority to optimize drug selection and improve patient outcomes. We performed transcriptomic and immune profiling on 158 tumor biopsies from melanoma patients treated with anti-PD-1 monotherapy (n = 63) or combined anti-PD-1 and anti-CTLA-4 (n = 57). These data identified activated T cell signatures and T cell populations in responders to both treatments. Further mass cytometry analysis identified an EOMES+CD69+CD45RO+ effector memory T cell phenotype that was significantly more abundant in responders to combined immunotherapy compared with non-responders (n = 18). The gene expression profile of this population was associated with longer progression-free survival in patients treated with single agent and greater tumor shrinkage in both treatments.Graphical Abstract