Co-targeting TGF-β and PD-L1 sensitizes triple-negative breast cancer to experimental immunogenic cisplatin-eribulin chemotherapy doublet
Laura Kalfeist, … , Emeric Limagne, Sylvain Ladoire
Laura Kalfeist, … , Emeric Limagne, Sylvain Ladoire
Published July 1, 2025
Citation Information: J Clin Invest. 2025;135(13):e184422. https://doi.org/10.1172/JCI184422.
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Research Article Immunology Oncology

Co-targeting TGF-β and PD-L1 sensitizes triple-negative breast cancer to experimental immunogenic cisplatin-eribulin chemotherapy doublet

Abstract

In preclinical mouse models of triple-negative breast cancer (TNBC), we show that a combination of chemotherapy with cisplatin (CDDP) and eribulin (Eri) was additive from an immunological point of view and was accompanied by the induction of an intratumoral immune and inflammatory response favored by the immunogenic cell death induced by CDDP, as well as by the vascular and tumor stromal remodeling induced by each chemotherapy. Unexpectedly, despite the favorable immune context created by this immunomodulatory chemotherapy combination, our models remained refractory to the addition of anti–PD-L1 immunotherapy. These surprising observations led us to discover that CDDP chemotherapy was simultaneously responsible for the production of TGF-β by several populations of cells present in tumors, which favored the emergence of different subpopulations of immune cells and cancer-associated fibroblasts characterized by immunosuppressive properties. Accordingly, co-treatment with anti–TGF-β restored the immunological synergy between this immunogenic doublet of chemotherapy and anti–PD-L1 in a CD8-dependent manner. Translational studies revealed the unfavorable prognostic effect of the TGF-β pathway on the immune response in human TNBC, as well as the ability of CDDP to induce this cytokine also in human TNBC cell lines, thus highlighting the clinical relevance of targeting TGF-β in the context of human TNBC treated with chemoimmunotherapy.

Authors

Laura Kalfeist, Fanny Ledys, Stacy Petit, Cyriane Poirrier, Samia Kada Mohammed, Loïck Galland, Valentin Derangère, Alis Ilie, David Rageot, Romain Aucagne, Pierre-Simon Bellaye, Caroline Truntzer, Marion Thibaudin, Mickaël Rialland, François Ghiringhelli, Emeric Limagne, Sylvain Ladoire

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Figure 5

TGF–β blockade restores chemoimmunotherapy efficacy.

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TGF–β blockade restores chemoimmunotherapy efficacy. (A–C) 4T1 (A), EMT6...
(A–C) 4T1 (A), EMT6 (B), and TS/A (C) tumor–bearing mice were treated with the CDDP-Eri doublet, anti–PD-L1 mAb, and anti–TGF-β mAb, or the combination of the 4 molecules, or left untreated. Tumor volume was monitored (schema). Data represent the mean ± SEM. Mouse survival was evaluated (n = at least 5 mice/group). Data represent the median; log-rank test. (D) MMTV-PyMT mice were treated with CDDP-Eri doublet, anti–PD-L1, and anti–TGF-β mAbs, or the combination of the 4 molecules, or left untreated at the appearance of the first tumor target lesion. Mouse survival was evaluated for 120 days (control: n = 13, CDDP-Eri: n = 7, anti–PD-L1/anti–TGF-β: n = 16, quadritherapy: n = 10). Data represent the median; log-rank test. The number of tumors was assessed for each mouse at day 29 after the different chemotherapy treatments. (E and F) 4T1 (E) and EMT6 (F) tumor–bearing mice were treated with CDDP-Eri and CDDP-Eri plus anti–PD-L1 with or without anti–TGF-β mAbs with or without CTL depletion. Tumor volume was monitored for at least 4 weeks after treatment (n = at least 3 mice/group). Box plots show the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA.