Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy

Cancer Cell. 2017 May 8;31(5):711-723.e4. doi: 10.1016/j.ccell.2017.04.003.

Abstract

Effector T cells have the capability of recognizing and killing cancer cells. However, whether tumors can become immune resistant through exclusion of effector T cells from the tumor microenvironment is not known. By using a tumor model resembling non-T cell-inflamed human tumors, we assessed whether adoptive T cell transfer might overcome failed spontaneous priming. Flow cytometric assays combined with intra-vital imaging indicated failed trafficking of effector T cells into tumors. Mechanistically, this was due to the absence of CXCL9/10, which we found to be produced by CD103+ dendritic cells (DCs) in T cell-inflamed tumors. Our data indicate that lack of CD103+ DCs within the tumor microenvironment dominantly resists the effector phase of an anti-tumor T cell response, contributing to immune escape.

Keywords: T cell-inflamed tumor microenvironment; adoptive T cell transfer; immune escape; immunotherapy resistance; non-T cell-inflamed tumor microenvironment.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Basic-Leucine Zipper Transcription Factors / deficiency
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemokine CXCL10 / metabolism
  • Chemokine CXCL9 / metabolism
  • Chemotaxis, Leukocyte*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Genotype
  • Immunologic Memory
  • Immunotherapy, Adoptive / methods*
  • Integrin alpha Chains / metabolism
  • Melanoma / immunology
  • Melanoma / metabolism
  • Melanoma / pathology
  • Melanoma / therapy*
  • Mice, Knockout
  • Phenotype
  • Repressor Proteins / deficiency
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Skin Neoplasms / immunology
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Skin Neoplasms / therapy*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / transplantation*
  • Time Factors
  • Tumor Burden
  • Tumor Escape*
  • Tumor Microenvironment
  • beta Catenin / metabolism

Substances

  • Antigens, CD
  • Basic-Leucine Zipper Transcription Factors
  • CTNNB1 protein, mouse
  • Chemokine CXCL10
  • Chemokine CXCL9
  • Cxcl10 protein, mouse
  • Cxcl9 protein, mouse
  • Integrin alpha Chains
  • Repressor Proteins
  • SNFT protein, human
  • SNFT protein, mouse
  • alpha E integrins
  • beta Catenin