Cellular reprogramming during anti-PD-1 and chemotherapy treatment in early-stage primary hormone receptor-positive breast cancer
The efficacy of immune checkpoint inhibitors combined with chemotherapy varies among breast cancer subtypes and is particularly less effective in hormone receptor-positive (HR + ) breast cancers. Here, we analyze pre-, on-, and post-treatment biopsies from 20 female patients with stage II-III HR+ breast cancer who participated in a clinical trial of neoadjuvant chemo-immunotherapy with nab-paclitaxel and pembrolizumab. Through single-nucleus RNA and ATAC sequencing of these tumor biopsies, we identified gene expression metaprograms (MPs) associated with differential therapy responses. Here we show that favorable responders exhibit increased activity in pathways related to tumor state transition, T cell effector functions, and pro-inflammatory macrophage states. Unfavorable responders demonstrate increased tumor estrogen signaling and immunosuppressive tumor-immune interactions. In this work, we highlight the interplay between tumor and microenvironmental cells in treatment naïve and exposed HR+ breast cancers and reveal that pivotal shifts in tumor cell, macrophage, and T cell states may mediate response to chemo-immunotherapy.
Authors
- Tanya E. Keenan (ORCID: https://orcid.org/0000-0001-5300-9998)
- Erica Pimenta (ORCID: https://orcid.org/0000-0002-9684-6486)
- Elizabeth A. Mittendorf (ORCID: https://orcid.org/0000-0002-9762-8536)
- Molly K. DiLullo (ORCID: https://orcid.org/0009-0005-1036-796X)
- Anwesha Nag (ORCID: https://orcid.org/0000-0002-1947-7429)
- Sébastien Vigneau (ORCID: https://orcid.org/0000-0002-9091-2067)
- Theodora Pappa
- Eileen Wrabel
- Eliezer M. Van Allen (ORCID: https://orcid.org/0000-0002-0201-4444)
- Breanna Titchen (ORCID: https://orcid.org/0000-0002-1569-0513)
- Aaron R. Thorner (ORCID: https://orcid.org/0000-0002-9160-7881)
- Rinath M. Jeselsohn (ORCID: https://orcid.org/0000-0001-7996-7529)
- Meredith Bemus
- Jingxin Fu (ORCID: https://orcid.org/0000-0002-4028-3661)
- Kevin Bi (ORCID: https://orcid.org/0000-0002-6794-1804)
- Sara M. Tolaney (ORCID: https://orcid.org/0000-0002-5940-8671)
- Erin Shannon (ORCID: https://orcid.org/0000-0001-8112-2373)
- Sabrina Y. Camp (ORCID: https://orcid.org/0000-0002-9695-5527)
- Adrienne Gropper Waks (ORCID: https://orcid.org/0000-0001-5649-7229)
- Daniel L. Abravanel (ORCID: https://orcid.org/0000-0002-0129-1618)
- Jihye Park (ORCID: https://orcid.org/0000-0002-4451-2046)
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Harvard University Press (US)
- Parker Institute for Cancer Immunotherapy (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
- Dana-Farber Brigham Cancer Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41467-025-66659-y
- Citations
- 2
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- Ambrose Monell Foundation
- Susan G. Komen
- National Institutes of Health
- National Cancer Institute