Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer

  • Cancer Cell. 2018 Mar 12;33(3):463-479.e10. doi: 10.1016/j.ccell.2018.01.011.
Ana Costa  1 ,  Yann Kieffer  1 ,  Alix Scholer-Dahirel  2 ,  Floriane Pelon  1 ,  Brigitte Bourachot  1 ,  Melissa Cardon  1 ,  Philemon Sirven  2 ,  Ilaria Magagna  1 ,  Laetitia Fuhrmann  3 ,  Charles Bernard  1 ,  Claire Bonneau  1 ,  Maria Kondratova  4 ,  Inna Kuperstein  4 ,  Andrei Zinovyev  4 ,  Anne-Marie Givel  1 ,  Maria-Carla Parrini  5 ,  Vassili Soumelis  6 ,  Anne Vincent-Salomon  3 ,  Fatima Mechta-Grigoriou  7
Affiliations
  • 1. Institut Curie, Stress and Cancer Laboratory, Equipe labelisée Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France.
  • 2. Institut Curie, Stress and Cancer Laboratory, Equipe labelisée Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France; Institut Curie, Integrative Biology of Human Dendritic Cells and T Cells Laboratory, PSL Research University, Inserm, U932, 26, rue d'Ulm, 75005 Paris, France.
  • 3. Department of Pathology, Institut Curie Hospital Group, 26, rue d'Ulm, 75248 Paris, France.
  • 4. Institut Curie, PSL Research University, Inserm, U900, Mines Paris Tech, Paris 75005, France.
  • 5. Analysis of Transduction Pathway, Institut Curie, Inserm, U830, PSL Research University, 26 rue d'Ulm, Paris 75005, France.
  • 6. Institut Curie, Integrative Biology of Human Dendritic Cells and T Cells Laboratory, PSL Research University, Inserm, U932, 26, rue d'Ulm, 75005 Paris, France.
  • 7. Institut Curie, Stress and Cancer Laboratory, Equipe labelisée Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. Electronic address: [email protected].
PMID: 29455927 DOI: 10.1016/j.ccell.2018.01.011
Abstract

Carcinoma-associated fibroblasts (CAF) are key players in the tumor microenvironment. Here, we characterize four CAF subsets in Breast Cancer with distinct properties and levels of activation. Two myofibroblastic subsets (CAF-S1, CAF-S4) accumulate differentially in triple-negative breast cancers (TNBC). CAF-S1 fibroblasts promote an immunosuppressive environment through a multi-step mechanism. By secreting CXCL12, CAF-S1 attracts CD4+CD25+ T lymphocytes and retains them by OX40L, PD-L2, and JAM2. Moreover, CAF-S1 increases T lymphocyte survival and promotes their differentiation into CD25HighFOXP3High, through B7H3, CD73, and DPP4. Finally, in contrast to CAF-S4, CAF-S1 enhances the regulatory T cell capacity to inhibit T effector proliferation. These data are consistent with FOXP3+ T lymphocyte accumulation in CAF-S1-enriched TNBC and show how a CAF subset contributes to Immunosuppression.

Keywords
CAF; FOXP3; T lymphocytes; Treg; breast cancers; fibroblasts; heterogeneity; regulatory T cell; stroma; triple-negative.