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Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma
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Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma
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Journal Article
Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma
2013
Overview
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.
Publisher
Elsevier Inc,Elsevier Limited,Nature Publishing Group
Subject
/ Antigens
/ Biology
/ Cells
/ Humans
/ Inflammation Mediators - metabolism
/ Male
/ Medicine
/ Membrane Proteins - genetics
/ Membrane Proteins - immunology
/ Membrane Proteins - metabolism
/ Mice
/ Original
/ Prostate
/ Proteins
/ 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
/ Tumors
