Evaluation of targeted and immune combination therapies in a rat model of hormone receptor-positive breast cancer

• 成果类型: Article
• 署名作者: Rojas-Jimenez, Ernesto; Bui, Triet M.; Yan, Pengze; Li, Zheqi; Seehawer, Marco; Nishida, Jun; Foidart, Pierre; Freeman, Gordon J.; Polyak, Kornelia
• 署名单位: Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2501052123
• 发表日期: 2026-02-10
• 页码: e2501052123
• 关键词: Breast cancer; hormone receptor positive; immune checkpoint inhibitor; targeted therapy; ENDOCRINE THERAPY; blockade; immunotherapy; resistance

摘要

Estrogen receptor (ER) positive breast cancer is the most prevalent subtype, commonly responsive to endocrine therapies. Immune checkpoint inhibitors (ICIs) have limited efficacy in ER-positive disease, highlighting the need for the development of combination immunotherapies for these patients. We previously established that nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats mimic immune evasive mechanisms and the heterogeneity of ICI response observed in patients. We identified a luminal growing gene signature in ER-positive tumors, which correlated with tumor growth and immune-related differences. Here, we evaluated targeting candidates from this signature KMT5B/C and IKBKE using inhibitors A-196 and IKBKEi respectively, alongside anti-estrogen (fulvestrant) and a TGF beta blocking antibody (NIS793), both individually and in combination with alpha PD-L1, within this rat model. Fulvestrant emerged as the most effective treatment, inducing regression of most existing tumors and reducing on-treatment tumor burden when combined with alpha PD-L1. A-196, while ineffective as a monotherapy, demonstrated enhanced response when combined with alpha PD-L1. Comprehensive tumor profiling through polychromatic flow cytometry and single-cell RNA sequencing revealed that A-196 induced a luminal-to-basal shift in tumor epithelial cells, enhancing antigen presentation, whereas epithelial-to-mesenchymal transition was linked to fulvestrant resistance. Our findings underscore the value of the rat mammary tumor model for preclinical studies in ER-positive breast cancer and advocate for the further validation and potential clinical development of KMT5B/C inhibitors to enhance the efficacy and broaden the applicability of ICI therapy in cancer patients.