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Background: Chemoimmunotherapy is a standard treatment for triple-negative breast cancer (TNBC), however, the impacts of different chemotherapies on T-cell populations, which could correlate with clinical activity, are not known. Quantifying T-cell populations with flow cytometry and T-cell receptor (TCR) immunosequencing may improve our understanding of how chemoimmunotherapy affects T-cell subsets, and to what extent clonal shifts occur during treatment. TCR immunosequencing of intratumoral T cells may facilitate the identification and monitoring of putatively tumor-reactive T-cell clones within the blood., Methods: Blood and tumor biopsies were collected from patients with metastatic TNBC enrolled in a phase Ib clinical trial of first or second-line pembrolizumab with paclitaxel or capecitabine. Using identical biospecimen processing protocols, blood samples from a cohort of patients treated for early-stage breast cancer were obtained for comparison. Treatment-related immunological changes in peripheral blood and intratumoral T cells were characterized using flow cytometry and TCR immunosequencing. Clonal proliferation rates of T cells were compared based on intratumoral enrichment., Results: When combined with pembrolizumab, paclitaxel and capecitabine resulted in similar time-dependent lymphodepletions across measured peripheral T-cell subsets. Their effects were more modest than that observed following curative-intent dose-dense anthracycline and cyclophosphamide (ddAC) (average fold-change in CD3 + cells, capecitabine: -0.42, paclitaxel: -0.56, ddAC: -1.21). No differences in T-cell clonality or richness were observed following capecitabine or paclitaxel-based treatments. Regression modeling identified differences in the emergence of novel T-cell clones that were not detected at baseline (odds compared with ddAC, capecitabine: 0.292, paclitaxel: 0.652). Pembrolizumab with paclitaxel or capecitabine expanded T-cell clones within tumors; however, these clones did not always expand within the blood. Proliferation rates within the blood were similar between clones that were enriched and those that were not enriched within tumors., Conclusion: Chemoimmunotherapy for metastatic TNBC with pembrolizumab and capecitabine or paclitaxel resulted in similar peripheral T-cell subset lymphodepletion without altering T-cell clonal diversity. Regression modeling methods are applicable in immune monitoring studies, such as this to identify the odds of novel T-cell clones emerging during treatment, and proliferation rates of tumor-enriched T-cell clones., Competing Interests: Competing interests: YK: Research support from Bristol Myers Squibb (BMS), GlaxoSmithKline, Shimadzu. WLR: Research support from Galectin Therapeutics, BMS, GlaxoSmithKline, Mi. NA Therapeutics, Inhibrx, Veana Therapeutics, Shimadzu, OncoSec Medical, Turn Biotechnologies, CanWell Pharma, Aeglea Biotherapeutics, and Calibr. Patents/Royalties: Galectin Therapeutics. Advisory Boards: Nektar Therapeutics, Vesselon. NP: Financial interest: Adaptive Biotechnologies. PAF: Financial interest: Adaptive Biotechnologies. WJU: Safety advisory board: Astra Zeneca. HLM: Research support: Merck, Lilly, BMS. Advisory/consultancy Merck, Lilly, Spectrum Pharmaceuticals, Amgen, Immunomedics, Pfizer, Genentech, BMS, Genomic Health, ZIOPHARM Oncology; Travel/expenses: Merck, Spectrum Pharmaceuticals, Lilly, Amgen, Immunomedics, Pfizer, Genentech Puma Biotechnology; Speaker Bureau: Lilly. Institutional funding: Merck, Lilly, BMS, ZIOPHARM Oncology DBP: Research support: BMS, Merck, Brooklyn ImmunoTherapeutics. Advisory Boards: BMS, Merck, Syndax, Nektar, Puma, Nanostring, Genetech, Brooklyn Immunotherapeutics, Sanofi, Biotheranostics, NGMBio, Lilly. Speaker Bureau: Genentech, Novartis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)