Peripheral blood mononuclear cell biomarkers predict response to immune checkpoint inhibitor therapy in metastatic breast cancer

Abstract

Background: The role of immune checkpoint PD-1/PD-L1 inhibitor (ICI) in breast cancer (BC) is being investigated in clinical trials. Preclinical evidence strongly supports the synergistic effects of CDK4/6 inhibitor and ICI. A phase II trial is testing the safety and efficacy of the combination of letrozole, palbociclib and pembrolizumab in patients with hormone receptor positive (HR+) BC (NCT02778685). Currently, there is no well-defined circulating biomarker to predict response to ICI. Methods: Peripheral blood mononuclear cells (PBMC) were collected at day 1 of cycles 1 (pre-treatment), 2, 4, 6 and 8. The comprehensive characterization of 14 innate cell types, 7 adaptive T-cells, and 16 exhaustion-related T-cells was performed using 15- color flow cytometry. Core biopsies were taken at baseline and optionally on-study to assess immune cell subsets. Results: Preliminary analysis included nine patients with the following responses by RECIST 1.1: 1 complete response, 4 partial responses, 2 stable disease, and 2 progression of disease. Analysis showed correlation of clinical response to high baseline levels of γδ T-cells (r=0.74, p=0.02) and exhausted T-cells: CD4+PD-1+KLRG1+ (r=0.74, p=0.02), CD4+PD-1+CD160+ (r=0.71, p=0.02), and CD4+PD-1+TIM3+ (r=0.71, p=0.03). Most patients showed a decrease in the number of CD33hi myeloid- derived suppressor cells (p=0.04) and CD4+PD-1+TIGIT+ exhausted T-cells (p=0.04) in peripheral blood at C2D1. Strong indicators of clinical response included increased CD33low myeloid-derived suppressor cells (r=0.70, p=0.04) and decreased type-1 CD8+ T-cells (r=0.81, p=0.009) at C4D1. Conclusions: High pre-treatment peripheral blood exhausted CD4+T-cells is associated with clinical response to ICI in HR+BC. Further analysis including tumor tissue immune profiling is currently ongoing to verify these findings.