Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma

Mol Ther. 2013 Aug;21(8):1611-20. doi: 10.1038/mt.2013.110. Epub 2013 Jun 4.

Abstract

Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cytokines / biosynthesis
  • Cytotoxicity, Immunologic
  • Disease Models, Animal
  • Fibroblasts / immunology*
  • Fibroblasts / metabolism
  • Gelatinases / genetics
  • Gelatinases / immunology*
  • Gelatinases / metabolism
  • Gene Expression
  • Gene Order
  • Genetic Vectors
  • Humans
  • Immunotherapy
  • Inflammation Mediators / metabolism
  • Lung / immunology
  • Lung / metabolism
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Receptors, Antigen / genetics
  • Receptors, Antigen / immunology*
  • Receptors, Antigen / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / immunology*
  • Serine Endopeptidases / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Cytokines
  • Inflammation Mediators
  • Membrane Proteins
  • Receptors, Antigen
  • Recombinant Fusion Proteins
  • Serine Endopeptidases
  • fibroblast activation protein alpha
  • Gelatinases