Cellular reprogramming during anti-PD-1 and chemotherapy treatment in early-stage primary hormone receptor-positive breast cancer

Jingxin Fu, Adrienne G. Waks, Erica Pimenta, Breanna Titchen, Kevin Bi, Sabrina Camp, Theodora Pappa, Tanya Keenan, Erin Shannon, Sébastien Vigneau, Meredith Bemus, Anwesha Nag, Aaron R. Thorner, Jihye Park, Molly DiLullo, Eileen Wrabel, Rinath Jeselsohn, Elizabeth A. Mittendorf, Daniel L. Abravanel, Sara M. Tolaney and Eliezer M. Van Allen ()
Additional contact information
Jingxin Fu: Dana-Farber Cancer Institute, Medical Oncology
Adrienne G. Waks: Dana-Farber Cancer Institute, Medical Oncology
Erica Pimenta: Dana-Farber Cancer Institute, Medical Oncology
Breanna Titchen: Dana-Farber Cancer Institute, Medical Oncology
Kevin Bi: Dana-Farber Cancer Institute, Medical Oncology
Sabrina Camp: Dana-Farber Cancer Institute, Medical Oncology
Theodora Pappa: Dana-Farber Cancer Institute, Medical Oncology
Tanya Keenan: Dana-Farber Cancer Institute, Medical Oncology
Erin Shannon: Dana-Farber Cancer Institute, Medical Oncology
Sébastien Vigneau: Dana-Farber Cancer Institute, Medical Oncology
Meredith Bemus: Dana-Farber Cancer Institute, Medical Oncology
Anwesha Nag: Dana-Farber Cancer Institute, Medical Oncology
Aaron R. Thorner: Dana-Farber Cancer Institute, Medical Oncology
Jihye Park: Dana-Farber Cancer Institute, Medical Oncology
Molly DiLullo: Dana-Farber Cancer Institute, Medical Oncology
Eileen Wrabel: Dana-Farber Cancer Institute, Medical Oncology
Rinath Jeselsohn: Dana-Farber Cancer Institute, Medical Oncology
Elizabeth A. Mittendorf: Dana-Farber Brigham Cancer Center, Breast Oncology Program
Daniel L. Abravanel: Dana-Farber Cancer Institute, Medical Oncology
Sara M. Tolaney: Dana-Farber Cancer Institute, Medical Oncology
Eliezer M. Van Allen: Dana-Farber Cancer Institute, Medical Oncology

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-66659-y

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