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 M Coussens; Brian Ruffell

doi:10.1016/j.ccell.2017.11.019

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.

Authors

Álvaro de Mingo Pulido¹, Alycia Gardner², Shandi Hiebler¹, Hatem Soliman³, Hope S Rugo⁴, Matthew F Krummel⁵, Lisa M Coussens⁶, Brian Ruffell⁷

Affiliations

¹ Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA.
² Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33620, USA.
³ Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
⁴ Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
⁵ Department of Pathology, University of California, San Francisco, CA 94143, USA.
⁶ Department of Cell, Developmental & Cancer Biology, and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
⁷ Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address: [email protected].

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding