title: Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte-associated molecule-4 blockade: the effect is manifested only at the restricted tumor-bearing stages.
abstract: Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), a second counterreceptor for the B7 family of costimulatory molecules, functions as a negative regulator of T-cell activation. Here, we investigated whether the blockade of the CTLA-4 function leads to enhancement of antitumor T-cell responses at various stages of tumor growth. Unfractionated spleen cells taken from CSAIM fibrosarcoma-bearing mice 1-2 weeks after CSA1M cell implantation (early tumor-bearing mice) contained tumor-primed T cells that produced interleukin 2 and IFN-gamma through collaboration with antigen-presenting cell-binding tumor antigens when cultured in vitro. However, this initial lymphokine-producing capacity decreased at later stages of tumor growth (7-10 weeks after tumor cell implantation). Anti-CTLA-4 monoclonal antibody (mAb) was added to whole-spleen cell cultures from early or late tumor-bearing mice. Spleen cells from early tumor-bearing mice exhibited enhanced production of interleukin 2 and IFN-gamma upon in vitro culture in the presence of anti-CTLA-4 mAb. However, addition of anti-CTLA-4 mAb to whole-spleen cell cultures from late tumor-bearing mice failed to display such an enhancement. Consistent with these in vitro results, the in vivo antitumor effect of anti-CTLA-4 administration was observed in a tumor-bearing stage-restricted manner; in vivo administration of anti-CTLA-4 (1 mg/mouse, three times at 1-week intervals) into early tumor-bearing mice resulted in regression of growing tumors, whereas the same treatment did not affect tumor growth when performed for late tumor-bearing mice. Similar anti-CTLA-4 effect was observed in another tumor (OV-HM ovarian carcinoma) model. These in vitro and in vivo results indicate that CTLA-4 blockade in tumor-bearing individuals enhances the capacity to generate antitumor T-cell responses, but the expression of such an enhancing effect is restricted to early stages of tumor growth.
authors.affiliation: Biomedical Research Center, Osaka University Medical School, Suita, Japan.
authors.forename: Y F
authors.initials: YF
authors.lastname: Yang
authors.forename: J P
authors.initials: JP
authors.lastname: Zou
authors.forename: J
authors.initials: J
authors.lastname: Mu
authors.forename: R
authors.initials: R
authors.lastname: Wijesuriya
authors.forename: S
authors.initials: S
authors.lastname: Ono
authors.forename: T
authors.initials: T
authors.lastname: Walunas
authors.forename: J
authors.initials: J
authors.lastname: Bluestone
authors.forename: H
authors.initials: H
authors.lastname: Fujiwara
authors.forename: T
authors.initials: T
authors.lastname: Hamaoka
mesh_terms: D000069594:Abatacept; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D060908:CTLA-4 Antigen; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology / Q000628:therapy; D007111:Immunity, Cellular; D018796:Immunoconjugates; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D000069594:Abatacept; D007371:Interferon-gamma