Clinical response to PD-1 blockade correlates with a sub-fraction of peripheral central memory CD4+ T cells in patients with malignant melanoma

Abstract

Cancer immunotherapy that blocks immune checkpoint molecules, such as PD-1/PD-L1, unleashes dysfunctional antitumor T-cell responses and has durable clinical benefits in various types of cancers. Yet its clinical efficacy is limited to a small proportion of patients, highlighting the need for identifying biomarkers that can predict the clinical response by exploring antitumor responses crucial for tumor regression. Here we explored T-cell responses associated with clinical benefits using peripheral blood mononuclear cells (PBMCs) from patients with malignant melanoma treated with anti-PD-1 monoclonal antibody (mAb). Pre- and post-treatment samples were collected from two different cohorts (discovery set and validation set) and subjected to mass cytometry assays that measured the expression levels of 35 proteins. Screening by high dimensional clustering in the discovery set identified increases in three micro-clusters of CD4⁺ T cells, a subset of central memory CD4⁺ T cells harboring CD27⁺FAS^-CD45RA^-CCR7⁺ phenotype, after treatment in long-term survivors, but not in non-responders. The same increase was also observed in clinical responders in the validation set. We propose that increases in this subset of central memory CD4⁺ T cells in peripheral blood can be potentially used as a predictor of clinical response to PD-1 blockade therapy in patients with malignant melanoma.