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 = 35; luminal, n = 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 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 are related to chemoimmunotherapy resistance, particularly in TNBC.

DongGeun Son, M.D., Ho Cheol Jang, M.D., Young Eun Lee, Ph.D., Yong Jun Choi, M.D., Joo Heon Park, M.D., Ha Jin Lim, M.D., Hyun-Jung Choi, M.D., Ph.D., Hee Jo Baek, M.D., Ph.D., Hoon Kook, M.D., Ph.D., Mihee Kim, M.D., Ph.D., Ga-Young Song, M.D., Ph.D., Seo-Yeon Ahn, M.D., Ph.D., Sung-Hoon Jung, M.D., Ph.D., Deok-Hwan Yang, M.D., Ph.D., Je-Jung Lee, M.D., Ph.D., Hyeonug-Joon Kim, M.D., Ph.D., Jae-Sook Ahn, M.D., Ph.D., and Myung-Geun Shin, M.D., Ph.D.. Ann Lab Med -0001;0:. https://doi.org/10.3343/alm.2024.0570

Chronic lymphocytic leukemia (CLL) is uncommon in Asia, and longitudinal genomic data from Asian cohorts are limited. We conducted serial whole-exome sequencing (WES) in a multicenter Korean cohort of newly diagnosed, elderly CLL treated with chlorambucil–obinutuzumab to evaluate mutational heterogeneity and clonal hematopoiesis of indeterminate potential (CHIP) during treatment and follow-up. Tumor-only variants were filtered, restricted to nonsynonymous or loss-of-function coding/splice-site mutations, and summarized as a binary patient-by-gene matrix for principal component analysis (PCA), trajectory analysis, and k-means clustering. CHIP was defined as ≥1 qualifying mutation in a prespecified CHIP gene set. Baseline PCA was more compact in patients with complete response at end of treatment, whereas partial response or progressive disease cases were more dispersed. PCA trajectories were compact and directionally consistent in complete responders, more dispersed in partial responders, and highly heterogeneous without a dominant direction in progressive disease. Clustering identified dispersed and compact clusters, and CHIP-associated mutations were enriched in the dispersed cluster (55.6% vs. 8.3%, Fisher’s exact p = 0.0086). In paired samples collected 3–5 months after end of treatment, CHIP status changed in some patients. Serial WES may provide complementary information to treatment response, although these observations require confirmation in larger cohorts.

Song GY, et al. J Korean Med Sci. 2026 Feb;41:e81. https://doi.org/10.3346/jkms.2026.41.e81

Table S3 from Proliferation of Tumor-Related Regulatory T Cells in Circulation Dictates Efficacy of Chemoimmunotherapy in Triple-Negative Breast Cancer