Integrin αvβ6-TGFβ-SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer

Cancer Cell. 2021 Jan 11;39(1):54-67.e9. doi: 10.1016/j.ccell.2020.12.001. Epub 2020 Dec 31.


Cancer immunotherapy shows limited efficacy against many solid tumors that originate from epithelial tissues, including triple-negative breast cancer (TNBC). We identify the SOX4 transcription factor as an important resistance mechanism to T cell-mediated cytotoxicity for TNBC cells. Mechanistic studies demonstrate that inactivation of SOX4 in tumor cells increases the expression of genes in a number of innate and adaptive immune pathways important for protective tumor immunity. Expression of SOX4 is regulated by the integrin αvβ6 receptor on the surface of tumor cells, which activates TGFβ from a latent precursor. An integrin αvβ6/8-blocking monoclonal antibody (mAb) inhibits SOX4 expression and sensitizes TNBC cells to cytotoxic T cells. This integrin mAb induces a substantial survival benefit in highly metastatic murine TNBC models poorly responsive to PD-1 blockade. Targeting of the integrin αvβ6-TGFβ-SOX4 pathway therefore provides therapeutic opportunities for TNBC and other highly aggressive human cancers of epithelial origin.

Keywords: SOX4 transcription factor; TGFβ; cancer immunotherapy; cytotoxic T cells; integrin αvβ6; therapy resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / pharmacology
  • Antigens, Neoplasm / genetics*
  • Antigens, Neoplasm / metabolism
  • Antineoplastic Agents, Immunological / therapeutic use*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Integrins / antagonists & inhibitors
  • Integrins / genetics*
  • Integrins / metabolism
  • Mice
  • Neoplasm Transplantation
  • SOXC Transcription Factors / genetics*
  • SOXC Transcription Factors / metabolism
  • Sequence Analysis, RNA
  • Signal Transduction / drug effects*
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / metabolism
  • Transforming Growth Factor beta / genetics
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / immunology
  • Tumor Escape* / drug effects
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • Antineoplastic Agents, Immunological
  • Integrins
  • SOX4 protein, human
  • SOXC Transcription Factors
  • Transforming Growth Factor beta
  • integrin alphavbeta6