Lipid-Associated Macrophages Are Induced by Cancer-Associated Fibroblasts and Mediate Immune Suppression in Breast Cancer

Eleonora Timperi, Paul Gueguen, Martina Molgora, Ilaria Magagna, Yann Kieffer, Silvia Lopez-Lastra, Philemon Sirven, Laura G. Baudrin, Sylvain Baulande, André Nicolas, Gabriel Champenois, Didier Meseure, Anne Vincent-Salomon, Anne Tardivon, Enora Laas, Vassili Soumelis, Marco Colonna, Fatima Mechta-Grigoriou, Sebastian Amigorena, Emanuela Romano

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Tumor-associated macrophages (TAM) play a detrimental role in triple-negative breast cancer (TNBC). In-depth analysis of TAM characteristics and interactions with stromal cells, such as cancer-associated fibroblast (CAF), could provide important biological and therapeutic insights. Here we identify at the single-cell level a monocyte-derived STAB1þTREM2high lipid-associated macrophage (LAM) subpopulation with immune suppressive capacities that is expanded in patients resistant to immune checkpoint blockade (ICB). Genetic depletion of this LAM subset in mice suppressed TNBC tumor growth. Flow cytometry and bulk RNA sequencing data demonstrated that coculture with TNBC-derived CAFs led to reprogramming of blood monocytes towards immune suppressive STAB1þTREM2high LAMs, which inhibit T-cell activation and proliferation. Cell-to-cell interaction modeling and assays in vitro demonstrated the role of the inflammatory CXCL12–CXCR4 axis in CAF–myeloid cell cross-talk and recruitment of monocytes in tumor sites. Altogether, these data suggest an inflammation model whereby monocytes recruited to the tumor via the CAF-driven CXCL12–CXCR4 axis acquire protumorigenic LAM capacities to support an immunosuppressive microenvironment.

Original languageEnglish
Pages (from-to)3291-3306
Number of pages16
JournalCancer research
Volume82
Issue number18
DOIs
StatePublished - Sep 15 2022

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