title: Mechanisms involved in synergistic anticancer effects of anti-4-1BB and cyclophosphamide therapy.
abstract: Chemotherapy can precondition for immunotherapy by creating an environment for homeostatic lymphoproliferation and eliminating some of the suppressive immune networks. We found that combination therapy with anti-4-1BB and cyclophosphamide (CTX) produced synergistic anticancer effects in the poorly immunogenic B16 melanoma model in mice. The antitumor effect of the combination therapy depended mainly on CD8(+) T cells, the 4-1BB-dependent expansion and differentiation of which into IFN-gamma-producing CD11c(+)CD8(+) T cells was enhanced by CTX. Anti-4-1BB induced a rapid repopulation of T and B cells from CTX-mediated lymphopenia. Anti-4-1BB protected naïve T cells from CTX and promoted proliferation of memory/effector and memory T cells. The combination treatment produced approximately 60- and 2.2-fold more CTLs per tumor-associated antigen compared with CTX or anti-4-1BB alone, respectively. This indicates that anti-4-1BB promoted a preferential expansion of tumor-specific CD8(+) T cells among the repopulated lymphocytes following CTX-mediated lymphopenia. CTX treatment enhanced 4-1BB expression on CD4 and CD8 T cells, and CTX alone or in combination with anti-4-1BB effectively suppressed peripheral regulatory T cells. Our results indicate that anti-4-1BB and CTX can be practical partners in cancer therapy because CTX creates an environment in which anti-4-1BB actively promotes the differentiation and expansion of tumor-specific CTLs.
authors.affiliation: Division of Cell and Immunobiology, and R&D Center for Cancer Therapeutics, National Cancer Center, Ilsan, Goyang, Kyounggi-do, Korea.
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.forename: Beom K
authors.initials: BK
authors.lastname: Choi
authors.forename: Ho S
authors.initials: HS
authors.lastname: Oh
authors.forename: Woo J
authors.initials: WJ
authors.lastname: Kang
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mittler
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D000939:Epitopes; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007156:Immunologic Memory / Q000187:drug effects; D008231:Lymphopenia / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000939:Epitopes; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D003520:Cyclophosphamide