title: MHC-class I-restricted CD4 T cells: a nanomolar affinity TCR has improved anti-tumor efficacy in vivo compared to the micromolar wild-type TCR.
abstract: Clinical studies with immunotherapies for cancer, including adoptive cell transfers of T cells, have shown promising results. It is now widely believed that recruitment of CD4(+) helper T cells to the tumor would be favorable, as CD4(+) cells play a pivotal role in cytokine secretion as well as promoting the survival, proliferation, and effector functions of tumor-specific CD8(+) cytotoxic T lymphocytes. Genetically engineered high-affinity T-cell receptors (TCRs) can be introduced into CD4(+) helper T cells to redirect them to recognize MHC-class I-restricted antigens, but it is not clear what affinity of the TCR will be optimal in this approach. Here, we show that CD4(+) T cells expressing a high-affinity TCR (nanomolar K                 (d) value) against a class I tumor antigen mediated more effective tumor treatment than the wild-type affinity TCR (micromolar K                 (d) value). High-affinity TCRs in CD4(+) cells resulted in enhanced survival and long-term persistence of effector memory T cells in a melanoma tumor model. The results suggest that TCRs with nanomolar affinity could be advantageous for tumor targeting when expressed in CD4(+) T cells.
authors.affiliation: Neuroscience Program, University of Illinois, Urbana, IL 61801, USA.
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Soto
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Stone
authors.forename: Adam S
authors.initials: AS
authors.lastname: Chervin
authors.forename: Boris
authors.initials: B
authors.lastname: Engels
authors.forename: Hans
authors.initials: H
authors.lastname: Schreiber
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; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D005805:Genes, MHC Class I / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma