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Cellular reprogramming during anti-PD-1 and chemotherapy treatment in early-stage primary hormone receptor-positive
Jingxin Fu1,2,3,4, Adrienne G Waks1,2,3, Erica Pimenta1
1Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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.
Insights
Chemo-immunotherapy response in hormone receptor-positive breast cancer is linked to specific cellular states. Favorable responses involve tumor transition and immune cell activity, while unfavorable responses show increased estrogen signaling and immunosuppression.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint inhibitors (ICIs) combined with chemotherapy show variable efficacy in breast cancer subtypes.
- Efficacy is notably lower in hormone receptor-positive (HR+) breast cancers.
Purpose of the Study:
- To analyze molecular changes in HR+ breast cancer during neoadjuvant chemo-immunotherapy.
- To identify gene expression metaprograms (MPs) associated with treatment response.
Main Methods:
- Single-nucleus RNA and ATAC sequencing of tumor biopsies from 20 HR+ breast cancer patients.
- Analysis of pre-, on-, and post-treatment samples from a clinical trial using nab-paclitaxel and pembrolizumab.
Main Results:
- Favorable responders displayed increased activity in tumor state transition, T cell effector functions, and pro-inflammatory macrophage states.
- Unfavorable responders showed elevated tumor estrogen signaling and immunosuppressive tumor-immune interactions.
- Identified pivotal shifts in tumor cell, macrophage, and T cell states mediating chemo-immunotherapy response.
Conclusions:
- Highlights the interplay between tumor and microenvironmental cells in HR+ breast cancer.
- Reveals key cellular state shifts that may determine response to neoadjuvant chemo-immunotherapy.
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