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

Álvaro de Mingo Pulido, Alycia Gardner, Shandi Hiebler, Hatem Soliman, Hope S. Rugo, Matthew F. Krummel, Lisa Coussens, Brian Ruffell

Research output: Contribution to journalArticle

58 Scopus citations

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. de Mingo Pulido et al. show that intratumoral CD103+ dendritic cells (DCs) highly express TIM-3. Anti-TIM-3 antibody promotes CXCL9 expression by these DCs, which enhances the function of CD8+ T cells, thereby improving paclitaxel's therapeutic activity in breast cancer models.

Original languageEnglish (US)
Pages (from-to)60-74.e6
JournalCancer Cell
Volume33
Issue number1
DOIs
StatePublished - Jan 8 2018

Keywords

  • breast cancer
  • chemotherapy
  • dendritic cells
  • galectin-9
  • immunotherapy
  • paclitaxel
  • TIM-3

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    de Mingo Pulido, Á., Gardner, A., Hiebler, S., Soliman, H., Rugo, H. S., Krummel, M. F., Coussens, L., & Ruffell, B. (2018). TIM-3 Regulates CD103+ Dendritic Cell Function and Response to Chemotherapy in Breast Cancer. Cancer Cell, 33(1), 60-74.e6. https://doi.org/10.1016/j.ccell.2017.11.019