title: Antitumor effects of anti-CD40/CpG immunotherapy combined with gemcitabine or 5-fluorouracil chemotherapy in the B16 melanoma model.
abstract: Our previous studies demonstrated that anti-CD40 mAb (anti-CD40) can synergize with CpG oligodeoxynucleotides (CpG) to mediate antitumor effects by activating myeloid cells, such as macrophages in tumor-bearing mice. Separate teams have shown that chemotherapy with gemcitabine (GEM) or 5-fluorouracil (5-FU) can reduce tumor-induced myeloid-derived suppressor cells (MDSC) in mice. In this study we asked if the same chemotherapy regimens with GEM or 5-FU will enhance the antitumor effect of anti-CD40 and CpG. Using the model of B16 melanoma growing intraperitoneally in syngeneic C57BL/6 mice, we show that these GEM or 5-FU treatment regimens reduced MDSC in the peritoneal cavity of tumor-bearing mice. Treatment of mice with GEM or 5-FU did not significantly affect the antitumor function of macrophages as assessed in vitro. In vivo, treatment with these GEM or 5-FU regimens followed by anti-CD40/CpG resulted in antitumor effects similar to those of anti-CD40/CpG in the absence of GEM or 5-FU. Likewise, reduction of MDSC by in vivo anti-Gr-1 mAb treatment did not significantly affect anti-CD40/CpG antitumor responses. Together, the results show that the GEM or 5-FU chemotherapy regimens did not substantially affect the antitumor effects induced by anti-CD40/CpG immunotherapy.
authors.affiliation: University of Wisconsin, Department of Human Oncology, Madison, WI, USA.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Qu
authors.forename: Mildred A R
authors.initials: MA
authors.lastname: Felder
authors.forename: Zulmarie
authors.initials: Z
authors.lastname: Perez Horta
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Rakhmilevich
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D019013:CD40 Antigens / Q000276:immunology*; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D007167:Immunotherapy; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009573:Nitrites / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000276:immunology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D047368:Tumor Burden / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000276:Adjuvants, Immunologic; D000964:Antimetabolites, Antineoplastic; D019013:CD40 Antigens; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D009573:Nitrites; D009838:Oligodeoxyribonucleotides; D003841:Deoxycytidine; D005472:Fluorouracil; D000093542:Gemcitabine
keywords: 5-Fluorouracil; Anti-CD40; CpG; Gemcitabine; Immunotherapy