title: Enhancement of antitumor immunity by combining anti-cytotoxic T lymphocyte             antigen-4 antibodies and cryotreated tumor lysate-pulsed dendritic cells in murine             osteosarcoma.
abstract: Immunotherapy with tumor lysate-loaded dendritic cells (DCs) is one of the             most promising strategies to induce antitumor immune responses. However, the antitumor             activity of cytotoxic T cells may be restrained by their expression of the inhibitory             T-cell coreceptor cytotoxic T lymphocyte antigen-4 (CTLA-4). By relieving this             restraint, CTLA-4-blocking antibodies promote tumor rejection, but the full scope             of their most suitable applications has yet to be fully determined. In the present             study, we offer proof of a preclinical concept in a C3H mouse osteosarcoma (LM8)             model that CTLA-4 blockade cooperates with cryotreated tumor lysate-pulsed DCs             in a primary tumor to prevent the outgrowth of lung metastasis. To evaluate immune             response activation, we established the following four groups of C3H mice (60 mice             in total): i) control immunoglobulin G (IgG)-treated mice; ii) tumor lysate-pulsed             DC-treated mice; iii) anti-CTLA-4 antibody-treated mice and iv) tumor lysate-pulsed             DC- and anti-CTLA-4 antibody-treated mice. The mice that received the tumor lysate-pulsed             DCs and anti-CTLA-4 antibody displayed reduced numbers of regulatory T lymphocytes             and increased numbers of CD8+ T lymphocytes inside the metastatic tumor, inhibition             of metastatic growth, a prolonged lifetime, reduced numbers of regulatory T lymphocytes             in the spleen and high serum interferon-γ levels. Combining an anti-CTLA-4 antibody             with tumor lysate-pulsed DCs enhanced the systemic immune response. To the best             of our knowledge, these findings document for the first time an effect of the             combination of tumor lysate-pulsed DCs and CTLA-4-blocking antibodies in osteosarcoma.             We suggest that cryotreated tumor lysate-pulsed DCs, although insufficient on             their own, may mediate the rejection of metastatic lesions and prevent recurrence             of the disease when combined with CTLA-4 blockade in osteosarcoma patients in             the clinical setting.
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita 879-5593, Japan. kawano@oita-u.ac.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawano
authors.forename: Ichiro
authors.initials: I
authors.lastname: Itonaga
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsumura
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology*; D002457:Cell Extracts / Q000008:administration & dosage / Q000276:immunology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D005615:Freezing; D007167:Immunotherapy; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D047368:Tumor Burden
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D002457:Cell Extracts; C556062:IL10 protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma