Synergistic Effects of Radiotherapy and PD‑1 Blockade in a Human‑Mimetic BRCAness Model of Triple-Negative Breast Cancer

TL;DR

This study shows that combining radiotherapy with PD-1 blockade can effectively treat BRCA1-deficient triple-negative breast cancer in a mouse model that mimics human disease.

Contribution

The study demonstrates a synergistic effect of radiotherapy and PD-1 blockade in a human-mimetic BRCAness model of TNBC.

Findings

PD-1 blockade delayed tumor progression and reduced proliferation while enhancing apoptosis in BRCA1-deficient TNBC.

Combining radiotherapy with PD-1 blockade significantly reduced extracellular matrix and increased T cell infiltration.

The model supports preclinical evaluation of combined DNA damaging agents and immunotherapy for BRCA1-associated breast cancer.

Abstract

BRCA1‑deficient triple‑negative breast cancer (TNBC) presents significant treatment challenges owing to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) targets, exhibits marked molecular heterogeneity that precludes the application of effective targeted therapies, and harbors a highly immunosuppressive tumor microenvironment. Here, we used the Brca1co/co MMTV‑Cre mouse model that recapitulates human BRCA1‑mutant TNBC, characterized by early dominance of CD11b⁺Gr‑1⁻F4/80Low blood‑derived macrophages and subsequent enrichment of F4/80High tissue macrophages within adipose‑rich mammary glands. PD‑1 blockade with anti‑mPD‑1 monoclonal antibodies (mAb) significantly delayed primary tumor progression, reduced proliferation marker levels (PCNA, Ki‑67), enhanced apoptosis (as indicated by increased cleaved PARP levels), and selectively impaired PI3K/AKT signaling. In a post‑resection setting, anti-mPD-1 treatment extended recurrence‑free survival rates, with elevated CD4, CD8α, and cleaved PARP levels observed in recurrent tumors. Mice with the longest relapse‑free intervals exhibited the strongest T cell marker expression. A combination of focal 20 Gy irradiation and PD-1 blockade exerted a potent synergistic effect. Specifically, irradiation reduced extracellular matrix deposition and enhanced tumor cell apoptosis (evidenced by increased cleaved caspase-3 and cytosolic PCNA) while PD-1 blockade stimulated robust inflammatory responses, in particular, expansion of CD8α⁺ T cell infiltration. These mechanistic insights align with clinical strategies for TNBC that integrate DNA damaging agents and immunotherapy and validate this model as an optimal in vivo platform for preclinical evaluation of novel treatment modalities for BRCA1‑associated breast cancer.

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