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. While anti-PD-1 therapy can be effective in patients with breast cancer, response varies and is often limited by the development of resistance. Here, the authors investigate molecular determinant of response and resistance using multiomic single nucleus sequencing of longitudinal biopsies taken from breast cancer patients on a phase II clinical trial investigating neoadjuvant chemotherapy and pembrolizumab (anti-PD-1).