title: Critical Roles of Chemoresistant Effector and Regulatory T Cells in Antitumor Immunity after Lymphodepleting Chemotherapy.
abstract: Antitumor immunity is augmented by cytotoxic lymphodepletion therapies. Adoptively transferred naive and effector T cells proliferate extensively and show enhanced antitumor effects in lymphopenic recipients. Although the impact of lymphodepletion on transferred donor T cells has been well evaluated, its influence on recipient T cells is largely unknown. The current study demonstrates that both regulatory T cells (Tregs) and effector CD8(+) T cells from lymphopenic recipients play critical roles in the development of antitumor immunity after lymphodepletion. Cyclophosphamide (CPA) treatment depleted lymphocytes more efficiently than other cytotoxic agents; however, the percentage of CD4(+)CD25(+) Foxp3(+) Tregs was significantly increased in CPA-treated lymphopenic mice. Depletion of these chemoresistant Tregs following CPA treatment and transfer of naive CD4(+) T cells augmented the antitumor immunity and significantly suppressed tumor progression. Further analyses revealed that recipient CD8(+) T cells were responsible for this augmentation. Using Rag2(-/-) mice or depletion of recipient CD8(+) T cells after CPA treatment abrogated the augmentation of antitumor effects in CPA-treated reconstituted mice. The transfer of donor CD4(+) T cells enhanced the proliferation of CD8(+) T cells and the priming of tumor-specific CD8(+) T cells originating from the lymphopenic recipients. These results highlight the importance of the recipient cells surviving cytotoxic regimens in cancer immunotherapies.
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Saida
authors.affiliation: Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan satoshi7@med.niigata-u.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Junko
authors.initials: J
authors.lastname: Baba
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Ko
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shoji
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Natsue
authors.initials: N
authors.lastname: Igarashi
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Rie
authors.initials: R
authors.lastname: Kondo
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Okajima
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Jun
authors.initials: J
authors.lastname: Koshio
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Ichikawa
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Nozaki
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ishikawa
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Koya
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miura
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Junta
authors.initials: J
authors.lastname: Tanaka
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kagamu
authors.affiliation: Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yoshizawa
authors.affiliation: Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Nakata
authors.affiliation: Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata 951-8520, Japan; and.
authors.forename: Ichiei
authors.initials: I
authors.lastname: Narita
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002945:Cisplatin / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology; D003603:Cytotoxins / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004351:Drug Resistance / Q000276:immunology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005354:Fibrosarcoma / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017239:Paclitaxel / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D014916:Whole-Body Irradiation; D000093542:Gemcitabine
chemical_list: D003603:Cytotoxins; D003841:Deoxycytidine; D008748:Methylcholanthrene; D005047:Etoposide; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine