What question did this study set out to answer?

The study aims to understand the role of non-immune stroma in breast cancer resistance to immunotherapy.

April 5, 2026

Abstract 6035: Non-immune stromal reprogramming shapes breast cancer immunotherapy resistance: insights from mouse models

Key Points

The study aims to understand the role of non-immune stroma in breast cancer resistance to immunotherapy.
Conducted single-cell RNA sequencing of CD45- cells from three breast cancer models with varied immunotherapy responses.
Analyzed stromal composition and functional programs related to cell signaling and communication.
Compared findings with human breast and lung cancer datasets.
Four distinct stromal states were associated with varying immunotherapy outcomes.
4T1 tumors showed fibroblast-dominant stroma with immune-silent endothelium.
EMT6 tumors demonstrated endothelial expansion and active CAFs.
EO771 tumors had quiescent vasculature and immune-stimulatory fibroblast profiles.
Identified fibroblast-associated signatures correlated with disease stage in human cohorts.

Abstract

Abstract Background: PD-1/PD-L1 blockade benefits only a subset of breast cancer patients.While tumor and immune cells have been extensively studied, the role of non-immunestroma such as endothelial cells (ECs) and cancer-associated fibroblasts (CAFs) intherapeutic resistance is less understood. Methods: We performed single-cell RNA sequencing of CD45- cells from threesyngeneic breast cancer models with divergent ICB responses (4T1: resistant, EMT6:partial responder, EO771: responder). Stromal composition, functional programs (GOBiological Process), and tumor-stroma paracrine communication (CellChat) wereanalyzed. Findings were compared with published human breast and lung cancerdatasets (Cell Res 30, 745-762 (2020)). Results: Distinct stromal states were linked to ICB outcomes. 4T1 were enriched forfibroblast- and extracellular matrix-dominant stroma with immune-silent endothelium,while EMT6 tumors showed endothelial expansion and interferon-active CAFs. EO771tumors displayed pericyte-stabilized, quiescent vasculature and immune-stimulatoryfibroblast programs. Pathway-level analysis highlighted conserved modes of stromalcommunication and identified fibroblast-associated signatures that correlated withdisease stage in human cohorts. Pathway-level analysis highlighted conserved modesof stromal communication and identified fibroblast-associated signatures that correlatedwith disease stage in human cohorts. Conclusions: Stromal reprogramming contributes to ICB resistance. Cross-speciesanalysis highlights endothelial and fibroblast states as potential biomarkers andtherapeutic entry points to enhance immunotherapy efficacy. Citation Format: Yujia Yue, Stephanie Mittman, Rohit Reja, Julia Lau, Minyi Shi, Ana Xavier-Magalhaes, Jonathan Paw, Carolina De Amat Herbozo, Marco De Simone, Yan Qu. Non-immune stromal reprogramming shapes breast cancer immunotherapy resistance: insights from mouse models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6035.

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Cite This Study

Yue et al. (Fri,) studied this question.

synapsesocial.com/papers/69d1fdbfa79560c99a0a40a5 https://doi.org/https://doi.org/10.1158/1538-7445.am2026-6035

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