Abstract 1188: Identification of CXCL10-inducing chemotherapy/targeted therapy combinations for PD-1 blockade sensitization in “cold” triple negative breast cancer
Authors: Kalfeist Laura , Petit Stacy , Galland Loick , Poirrier Cyriane , Aucagne Romain , Ghiringhelli François , Ladoire Sylvain , Limagne Emeric 
Published: March 2024

Abstract
Metastatic triple-negative breast cancer (mTNBC) currently has the poorest prognosis among subtypes, with limited treatment options due to molecular characteristics that render conventional targeted therapies ineffective. Immunotherapy, specifically anti-PD-(L)1 (ICIs), has revolutionized certain cancer treatments, but its efficacy in mTNBC has been disappointing. To enhance tumor responses to ICIs, combining them with immunogenic chemotherapy has been explored. Studies like IMpassion130 and KEYNOTE 522 indicate benefits of chemo-immunotherapy based on taxanes, especially in PD-L1+ tumors. PD-L1 expression often correlates with TILs infiltration, particularly cytotoxic T lymphocytes (CTLs), indicating an activated immune response in the tumor. However, tumors with poor CTL infiltration, known as "Cold" phenotype, are often associated with a lack of induction of CXCR3-associated chemokines (CXCL9, 10, and 11), crucial for CTLs recruitment in the tumor microenvironment. The limited efficacy of chemo-immunotherapy in PD-L1-negative tumors may stem from chemotherapy's inability to induce immunogenic cancer cell death, CXCR3-associated chemokines, and CTL recruitment. Internal data from a 4T1 TNBC murine model demonstrated that the taxane paclitaxel failed to induce CXCL10, CTL recruitment, and sensitization to PD-L1 blockade. The preclinical research project aimed to identify a combination therapy, inspired by current clinical practices, capable of inducing CXCL10 expression and restoring CTL recruitment in the 4T1 "cold" mTNBC model. We initially screened standard TNBC chemotherapies and selected carboplatin for its in vitro potential to induce CXCL10 production and its clinical use in association with ICIs in the TNBC. Combining carboplatin with a library of over 400 targeted therapies, we identified histone deacetylase (HDAC) inhibitors as significantly enhancing CXCL10 secretion. In vivo, this combination demonstrated therapeutic additivity, increasing immune recruitment, particularly CD8+ T lymphocytes, with the therapeutic effect reduced by CXCR3 blockade. Mechanistic exploration in vitro revealed that the combination activated the type I interferon pathway, inducing CXCL10 secretion. In vivo confirmation validated the role of the type I interferon pathway and CXCL10 in the combination's efficacy. This data outlines a chemotherapy and HDAC inhibitor combination capable of inducing CTL recruitment via increased CXCL10 production. Future project phases will focus on understanding HDACi's mechanism of action on CXCL10 production and the combination's potential to sensitize tumors to ICIs. Overall, this project underscores the role of epigenetic modifications in amplifying carboplatin-induced CXCL10 secretion, potentially converting "cold" ICI-resistant tumors into a "hot" phenotype.
Citation Format: Laura Kalfeist, Stacy Petit, Loick Galland, Cyriane Poirrier, Romain Aucagne, François Ghiringhelli, Sylvain Ladoire, Emeric Limagne. Identification of CXCL10-inducing chemotherapy/targeted therapy combinations for PD-1 blockade sensitization in “cold” triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1188.