title: Positive conversion of negative signaling of CTLA4 potentiates antitumor efficacy of adoptive T-cell therapy in murine tumor models.
abstract: Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been known to be a strong tolerance-inducing inhibitory receptor on T-cell surface. Systemic blocking of CTLA4 function with blocking antibodies has been regarded as an attractive strategy to enhance antitumor immunity. However, this strategy accompanies systemic autoimmune side effects that are sometimes problematic. Therefore, we developed a novel CTLA4 mutant that could be expressed in tumor antigen-specific T cells to enhance antitumor effect without systemic autoimmunity. This mutant, named CTLA4-CD28 chimera, consists of extracellular and transmembrane domains of CTLA4, linked with cytoplasmic CD28 domain. Overexpression of CTLA4-CD28 chimera in T cells delivered stimulatory signals rather than inhibitory signals of CTLA4 and significantly enhanced T-cell reactivity. Although this effect was observed in both CD4 and CD8 T cells, the effect on CD4 T cells was predominant. CTLA4-CD28 chimera gene modification of CD4 T cells significantly enhanced antitumor effect of unmodified CD8 T cells. Nonetheless, the gene modification of CD8 T cells along with CD4 T cells further maximized antitumor effect of T cells in 2 different murine tumor models. Thus, CTLA4-CD28 chimera gene modification of both tumor antigen-specific CD4 and CD8 T cells would be an ideal way of modulating CTLA4 function to enhance tumor-specific T-cell reactivity.
authors.affiliation: Specific Organs Cancer Branch.
authors.forename: Jae Hun
authors.initials: JH
authors.lastname: Shin
authors.forename: Hyung Bae
authors.initials: HB
authors.lastname: Park
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Oh
authors.forename: Dong Pyo
authors.initials: DP
authors.lastname: Lim
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Hae Hyun
authors.initials: HH
authors.lastname: Seo
authors.forename: Sang Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Hyeon Seok
authors.initials: HS
authors.lastname: Eom
authors.forename: In-Hoo
authors.initials: IH
authors.lastname: Kim
authors.forename: Seung Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Kyungho
authors.initials: K
authors.lastname: Choi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D019169:Jurkat Cells; D008223:Lymphoma / Q000276:immunology / Q000628:therapy; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D060908:CTLA-4 Antigen