title: A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control.
abstract: Adoptive transfer of genetically modified T cells to treat cancer has shown promise in several clinical trials. Two main strategies have been applied to redirect T cells against cancer: (1) introduction of a full-length T cell receptor (TCR) specific for a tumor-associated peptide-MHC, or (2) introduction of a chimeric antigen receptor, including an antibody fragment specific for a tumor cell surface antigen, linked intracellularly to T cell signaling domains. Each strategy has advantages and disadvantages for clinical applications. Here, we present data on the in vitro and in vivo effectiveness of a single-chain signaling receptor incorporating a TCR variable fragment as the targeting element (referred to as TCR-SCS). This receptor contained a single-chain TCR (Vα-linker-Vβ) from a high-affinity TCR called m33, linked to the intracellular signaling domains of CD28 and CD3ζ. This format avoided mispairing with endogenous TCR chains and mediated specific T cell activity when expressed in either CD4 or CD8 T cells. TCR-SCS-transduced CD8-negative cells showed an intriguing sensitivity, compared to full-length TCRs, to higher densities of less stable pepMHC targets. T cells that expressed this peptide-specific receptor persisted in vivo, and exhibited polyfunctional responses. Growth of metastatic antigen-positive tumors was significantly inhibited by T cells that expressed this receptor, and tumor cells that escaped were antigen-loss variants. TCR-SCS receptors represent an alternative targeting receptor strategy that combines the advantages of single-chain expression, avoidance of TCR chain mispairing, and targeting of intracellular antigens presented in complex with MHC proteins.
authors.affiliation: Department of Biochemistry, University of Illinois, 600 S. Mathews Ave., Urbana, IL, 61801, USA.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Stone
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Harris
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Soto
authors.forename: Adam S
authors.initials: AS
authors.lastname: Chervin
authors.forename: David H
authors.initials: DH
authors.lastname: Aggen
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Roy
authors.forename: David M
authors.initials: DM
authors.lastname: Kranz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008285:Major Histocompatibility Complex; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014161:Transduction, Genetic
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D016207:Cytokines; D016693:Receptors, Antigen, T-Cell, alpha-beta
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