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 1

The CDDP-Eri doublet increases tumor CTL infiltration and functionality.

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The CDDP-Eri doublet increases tumor CTL infiltration and functionality....
(A) 4T1 and EMT6 tumor–bearing mice were treated with CDDP, Eri, or CDDP-Eri, and tumor volume was monitored for 30 days (n ≥10 for 4T1; n ≥5 for EMT6). (B) CTL proportions were assessed by flow cytometry in tumors collected at days 4, 8, and 14 after treatment (n ≥5/group). (C) At day 8, CTLs were visualized by IHC and quantified using QPath (scale bars: 200 μm; n ≥6 for 4T1; n ≥5 for EMT6). Images are shown again in Supplemental Figure 2C. (D and F) CTL functionality was evaluated by measuring GzmB, TNF-α, and IFN-γ expression in 4T1 (D) and EMT6 (F) tumors. Representative dot plots and mean values are shown. (E and G) Activation/proliferation markers (PD-1, TIM-3, and Ki67) were analyzed in 4T1 (E) and EMT6 (G) tumors using flow cytometry, with representative dot plots at day 8 (left) and mean values (right). (H) PD-L1 expression on CD45− tumor cells was quantified by flow cytometry (n ≥4/group). (I) Immune-related gene expression was assessed by NanoString for total tumor mRNA. Heatmap shows normalized z scores, and volcano plots indicate statistical significance (n = 6/group). Box plots show the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA. orth., orthotopic.