AKAP12 positive fibroblast determines immunosuppressive contexture and immunotherapy response in patients with TNBC by promoting macrophage M2 polarization

Abstract

Background Triple-negative breast cancer (TNBC) is a molecular subtype of breast cancer with high aggressiveness and poor prognosis. Cancer-associated fibroblasts (CAFs) are major components of the TNBC microenvironment and play an important role in tumor progression and treatment responses. Our goal is to identify specific CAFs subpopulations contributing to TNBC development.Methods Multiomics analyses were applied to identify the CAFs-specific genes related to immunotherapy response. The clinical significance of a CAFs subset with A-kinase anchoring protein 12 (AKAP12) positive was explored in 80 patients with TNBC through double-labeling immunofluorescence assay. Cytometry by time-of-flight and RNA sequencing were performed to elucidate the immune landscape of TNBC microenvironment and functional mechanism of AKAP12+ CAFs.Results Multiomics analyses identified an AKAP12+ CAFs subset associated with the immunotherapy response of TNBC, and a high population of these cells is correlated with poor prognosis in patients with TNBC. Intratumoral AKAP12+ CAFs promote formation of an immunosuppressive tumor microenvironment by spatially mediating macrophage M2 polarization via interleukin-34 (IL-34)/macrophage-colony stimulating factor receptor (CSF1R) signaling in TNBC. Single-cell RNA sequencing analyses revealed that AKAP12+ fibroblasts interact with macrophages through the PI3K/AKT/IL-34 axis. In addition, pharmacological blockade of the IL-34/CSF1R signaling enhances the efficacy of anti-programmed cell death protein-1 antibody in TNBC rodent models.Conclusions AKAP12 is mainly expressed in fibroblasts in TNBC. AKAP12+ CAFs population is negatively associated with the prognosis of patients with TNBC. AKAP12+ CAFs shape the immunosuppressive TNBC microenvironment by releasing IL-34 to promote macrophage M2 polarization. Targeting IL-34 may boost the immunotherapeutic efficacy for TNBC.