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. Epub 2018 Feb 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / immunology
  • Cell Differentiation / physiology
  • Cell Proliferation / physiology
  • Fibroblasts / immunology*
  • Forkhead Transcription Factors / immunology
  • Humans
  • Immune Tolerance / immunology
  • Lymphocyte Activation / physiology
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Microenvironment / immunology*

Substances

  • Forkhead Transcription Factors