HTRA1+ macrophages induce T cells egress through CRIP1/NF-κB/CXCL12 to limit the effects of immunotherapy in triple-negative breast cancer
Menée à l'aide de modèles murins de cancer mammaire triple négatif, cette étude met en évidence un mécanisme par lequel une sous-population de macrophages HTRA1+, en induisant la migration des lymphocytes T via la voie de signalisation impliquant CRIP1, NF-kappaB et CXCL12, limite les effets de l'immunothérapie
The variation in immunotherapy responses among patients with triple-negative breast cancer (TNBC) is attributed to the high heterogeneity of tumor immune components, in which macrophages play a key role. Hence, identification of key macrophage subpopulations associated with immunotherapy efficacy could provide important biological and therapeutic insights. Here, using single-cell and spatial transcriptomes, we identified at the single-cell level, a subpopulation of macrophages related to T cell expansion during immunotherapy, characterized by high temperature requirement A1 (HTRA1) high expression and correlated with clinical and immunotherapy outcomes in TNBC. Loss of macrophage-specific Htra1 in transgenic mouse resulted in delayed TNBC growth, improved immunotherapy efficacy, and increased CD8+ T cell infiltration. Mechanistically, HTRA1 associated with cysteine-rich protein 1 (CRIP1) to facilitate CRIP1 binding to NF-
κB, thereby activating NF-κB pathway and downstream CXCL12 transcription, leading to T cell exit from tumors. Endothelial cell-derived CX3CL1 was implicated in the recruitment of HTRA1+ macrophages to tumor sites. Pharmacological antagonism of CXCL12/CXCR4 axis potentiated the immunotherapy efficacy in orthotopic TNBC mouse models. In conclusion, this study highlights a HTRA1+ macrophage subpopulation that can limit T cell infiltration and immunotherapy efficacy via the CXCL12/CXCR4 axis, which offers new leads to improve immunotherapeutic interventions in TNBC.
Cancer Immunology Research , résumé, 2026