Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy

Immunity. 2018 Jul 17;49(1):178-193.e7. doi: 10.1016/j.immuni.2018.06.006. Epub 2018 Jun 26.

Abstract

The biological and functional heterogeneity between tumors-both across and within cancer types-poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy.

Publication types

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

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Adenocarcinoma / therapy*
  • Aged
  • Aged, 80 and over
  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Epigenomics
  • Female
  • Gene Expression Profiling
  • Humans
  • Immunologic Factors / genetics
  • Immunologic Factors / immunology*
  • Immunotherapy*
  • Lymphocyte Subsets / immunology*
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Male
  • Mice
  • Middle Aged
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy*
  • Primary Cell Culture
  • Tumor Microenvironment / immunology*

Substances

  • Immunologic Factors

Supplementary concepts

  • Pancreatic Carcinoma