Proliferation of Tumor-Related Regulatory T Cells in Circulation Dictates Efficacy of Chemoimmunotherapy in Triple-Negative Breast Cancer

Purpose: PD-1/PD-L1 blockade modulates the responses of T cells, including regulatory T cells (Treg). Understanding the changes of Treg upon PD-1/PD-L1 blockade in patients with cancer and their association with therapeutic response will provide clues about the mechanisms underlying resistance to treatment. Experimental Design: Peripheral blood samples were acquired before and at 1 week following treatment from 65 patients [triple-negative (TN), n ¼ 35; luminal, n ¼ 30] enrolled in the KORNELIA phase II trial, which evaluated the efficacy of chemoimmunotherapy combining nivolumab and eribulin in patients with HER2-negative breast cancer. The immunophenotype of circulating immune cells was analyzed by flow cytometry. T-cell receptor sequencing was used to track the clonotypes of circulating Treg in relation to the tumor-related clonotypes. Results: In both breast cancer subtypes, chemoimmunotherapy increased the proportion of circulating Treg as well as their proliferative response. Notably, we observed an increased frequency of the circulating Treg population with tumor-related clonotypes after treatment in triple-negative breast cancer (TNBC). Moreover, increased proliferation of circulating Treg was associated with poor response to treatment, only in TNBC. This association between circulating Treg proliferation and poor clinical response was further supported by the analysis of publicly available single-cell transcriptomic data from patients with TNBC. A Treg-based bio-marker predicted both clinical response and survival outcomes in TNBC. Conclusions: Our results indicate that the proliferation and expansion of tumor-related clonotypes among circulating Treg are related to chemoimmunotherapy resistance, particularly in TNBC.