Continuous replenishment of the dysfunctional CD8 T cell axis is associated with response to chemoimmunotherapy in advanced breast cancer
Chemotherapy combined with immune checkpoint blockade has shown clinical activity in breast cancer. Response, however, occurs in only a low proportion of patients. How the immune landscape of the tumor determines the immune and clinical responses to chemoimmunotherapy is not well understood. Here, using a combination of single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq), we profile 40 biopsies from 27 patients with metastatic triple-negative breast cancer (TNBC), receiving chemotherapy and anti-PD-L1 alone or in combination with anti-CD73, in a phase 2 randomized clinical trial. Our results show an enrichment of late-dysfunctional, clonally expanded CD8<sup>+</sup> T cells in responder (R) patients. On treatment, R display an influx of newly emerging clonotypes, as well as expansion of the CD8<sup>+</sup> precursors. Collectively, our data suggest that baseline clonal expansion could be a potential predictor of response and that both clonal reinvigoration of pre-existing tumor-reactive T cells and clonal replacement on-treatment are important for a protective response to chemoimmunotherapy.
Authors
- Joshua J. Waterfall (ORCID: https://orcid.org/0000-0002-3762-5050)
- Pierre‐Emmanuel Bonté (ORCID: https://orcid.org/0000-0002-9732-5826)
- Sebastián Amigorena (ORCID: https://orcid.org/0000-0001-8583-8416)
- Aleksandra M. Walczak (ORCID: https://orcid.org/0000-0002-2686-5702)
- Kevin Punie (ORCID: https://orcid.org/0000-0002-1162-7963)
- Eleonora Timperi (ORCID: https://orcid.org/0000-0002-8357-6587)
- Laurence Buisseret (ORCID: https://orcid.org/0000-0002-3751-0819)
- Hans Wildiers (ORCID: https://orcid.org/0000-0001-8990-7837)
- Christina Metoikidou (ORCID: https://orcid.org/0000-0002-7294-5981)
- В. К. Карнаухов (ORCID: https://orcid.org/0000-0001-9463-8053)
- Christos Sotiriou (ORCID: https://orcid.org/0000-0002-5745-9977)
- Thierry Mora (ORCID: https://orcid.org/0000-0002-5456-9361)
- Viktorija Labroska
- Olivier Lantz (ORCID: https://orcid.org/0000-0003-3161-7719)
- Philippe Aftimos (ORCID: https://orcid.org/0000-0001-9946-4726)
- Diether Lambrechts (ORCID: https://orcid.org/0000-0002-3429-302X)
- Emanuela Romano (ORCID: https://orcid.org/0000-0002-1574-5545)
- Bram Boeckx (ORCID: https://orcid.org/0000-0002-0296-6680)
- Martine Piccart (ORCID: https://orcid.org/0000-0001-9068-8504)
- Xiaoxiao Wang (ORCID: https://orcid.org/0000-0002-3996-7900)
- Ling Wang (ORCID: https://orcid.org/0000-0001-7451-6876)
- Mingwei Wang (ORCID: https://orcid.org/0000-0001-9060-5107)
- Benoît Albaud
- Delphine Loirat
- Marion Espenel
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Libre de Bruxelles (BE)
- Inserm (FR)
- Université Paris Cité (FR)
- Université Paris Sciences et Lettres (FR)
- Institut Jules Bordet (BE)
- École Normale Supérieure - PSL (FR)
- Sorbonne Université (FR)
- Sorbonne Paris Cité (FR)
- VIB-KU Leuven Center for Cancer Biology (BE)
- École Normale Supérieure (BI)
- Immunité et Cancer (FR)
- National Center for Drug Screening (CN)
- Institut Curie (FR)
- KU Leuven (BE)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1016/j.xcrm.2025.101973
- Citations
- 2
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- Ligue Contre le Cancer
- Institut National Du Cancer