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 (TREG) cells. Understanding the changes of TREG cells upon PD-1/PD-L1 blockade in cancer patients and their association with therapeutic response will provide clues regarding the mechanisms underlying resistance to treatment. Experimental Design: Peripheral blood samples were acquired before and at 1-week post-treatment from 65 patients (triple-negative [TN], n = 35; luminal, n = 30) enrolled in KORNELIA phase 2 trial, which evaluated the efficacy of chemoimmunotherapy combining nivolumab and eribulin in HER2 negative breast cancer (BC) patients. Immunophenotype of circulating immune cells was analyzed using flow cytometry. T-cell receptor sequencing was used to track the clonotypes of circulating TREG cells in relation to the tumor-related clonotypes. Results: In both breast cancer subtypes, chemoimmunotherapy increased the proportion of circulating TREG cells as well as their proliferative response. Notably, we observed an increased frequency of the circulating TREG-cell population with tumor-related clonotypes after treatment in TNBC. Moreover, increased proliferation of circulating TREG cells was associated with poor response to treatment, only in TNBC. This association between circulating TREG-cell proliferation and poor clinical response was further supported by analysis of publicly available single-cell transcriptomic data from TNBC patients. A TREG-cell-based biomarker 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 cells are related to chemoimmunotherapy resistance particularly in TNBC.