title: Preimmunization of donor lymphocytes enhances antitumor immunity of autologous hematopoietic stem cell transplantation.
abstract: Lymphopenia-induced homeostatic proliferation (HP) of T cells following autologous hematopoietic stem cell transplantation (HSCT) skews the T-cell repertoire by engaging tumor-associated antigens (TAAs), leading to an induction of antitumor immunity. Here, as the tumor-reactive lymphocytes preferentially proliferate during the condition of HP, we examined whether the priming of a donor lymphocytes to TAAs could enhance HP-induced antitumor immunity in autologous HSCT recipients. First, to examine whether the tumor-bearing condition of donor influences the antitumor effect of HSCT, the lymphocytes isolated from CT26 tumor-bearing mice were infused into lethally irradiated mice. The growth of tumors was substantially suppressed in the mice that received HSCT from a tumor-bearing donor compared with a naïve donor, suggesting that a fraction of donor lymphocytes from tumor-bearing mice are primed in response to TAAs and remain responsive upon transplantation. We previously reported that type I interferon (IFN) maturates the dendritic cells and promotes the priming of T cells. We then investigated whether the further priming of donor cells by IFN-α can strengthen the antitumor effect of HSCT. The intratumoral IFN-α gene transfer significantly increased the number of IFN-γ-positive lymphocytes in response to CT26 cells but not the syngeneic lymphocytes in donor mice. The infusion of primed donor lymphocytes markedly suppressed the tumor growth in recipient mice, and cured 64% of the treated mice. Autologous HSCT with the infusion of primed donor lymphocytes is a promising strategy to induce an effective antitumor immunity for solid cancers.
authors.affiliation: Division of Gene and Immune Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; Department of Pediatrics, Fukui University School of Medicine, 23-3 Shimoaizuki, Matsuoka, Yoshida-gun, Fukui, 910-1193, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kouichirou
authors.initials: K
authors.lastname: Aida
authors.forename: Reina
authors.initials: R
authors.lastname: Miyakawa
authors.forename: Kenta
authors.initials: K
authors.lastname: Narumi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Udagawa
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Yusei
authors.initials: Y
authors.lastname: Ohshima
authors.forename: Kazunori
authors.initials: K
authors.lastname: Aoki
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D017710:Lymphocyte Transfusion / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D000951:Antigens, Neoplasm; D016898:Interferon-alpha
keywords: Donor; gene therapy; hematopoietic stem cell transplantation; interferon-alpha; preimmunization