Antimitotic chemotherapy promotes tumor NF-kB secretory phenotype and immunosuppressive CXCR2+ neutrophils chemotaxis in triple-negative breast cancers

Abstract

Integrated approaches that help understand how tumors, as immune-surveilled ecosystems, respond to chemotherapy are crucial for developing effective antitumor treatments. We previously showed, in immunodeficient context, that antimitotic chemotherapy induced cGAS/STING pathway amplifying antitumor response through a paracrine IFN-1 secretome. We herein studied tumor progression and response to treatment using an immunocompetent murine model. scRNAseq analysis revealed that paclitaxel treatment altered tumor cell phenotypes, favoring tumor cells with a gene expression signature indicative of active NF-{kappa}B pathway with secretory phenotype. Treatment coincidently reduced IFN-I signature cells during tumor progression. The resulting secretory shift correlated with neutrophil recruitment to the tumor, particularly CXCR2+ neutrophils, thereby contributing to an immunosuppressive microenvironment. Pharmacological inhibition of CXCR2 receptor by navarixin reactivated antitumor immunity, enhancing NK cell infiltration and tumor cytotoxicity. Navarixin combination with paclitaxel significantly reduced tumor volume and metastasis. Targeting the NF-{kappa}B-driven secretory phenotype, in particular through neutrophil modulation, holds promise for improving TNBC treatment outcomes.