TIM-3 Regulates CD103+ Dendritic Cell Function and Response to Chemotherapy in Breast Cancer

Cancer Cell. 2018 Jan 8;33(1):60-74.e6. doi: 10.1016/j.ccell.2017.11.019.

Abstract

Intratumoral CD103+ dendritic cells (DCs) are necessary for anti-tumor immunity. Here we evaluated the expression of immune regulators by CD103+ DCs in a murine model of breast cancer and identified expression of TIM-3 as a target for therapy. Anti-TIM-3 antibody improved response to paclitaxel chemotherapy in models of triple-negative and luminal B disease, with no evidence of toxicity. Combined efficacy was CD8+ T cell dependent and associated with increased granzyme B expression; however, TIM-3 expression was predominantly localized to myeloid cells in both human and murine tumors. Gene expression analysis identified upregulation of Cxcl9 within intratumoral DCs during combination therapy, and therapeutic efficacy was ablated by CXCR3 blockade, Batf3 deficiency, or Irf8 deficiency.

Keywords: TIM-3; breast cancer; chemotherapy; dendritic cells; galectin-9; immunotherapy; paclitaxel.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / immunology*
  • Basic-Leucine Zipper Transcription Factors / deficiency
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Dendritic Cells / immunology*
  • Female
  • Hepatitis A Virus Cellular Receptor 2 / genetics*
  • Humans
  • Integrin alpha Chains / immunology*
  • Interferon Regulatory Factors / immunology
  • Mice, Transgenic

Substances

  • Antigens, CD
  • Basic-Leucine Zipper Transcription Factors
  • HAVCR2 protein, human
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Integrin alpha Chains
  • Interferon Regulatory Factors
  • alpha E integrins
  • interferon regulatory factor-8