Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors.
Cytotoxic chemotherapy is generally considered immunosuppressive, with neutropenia and lymphopenia being common adverse side effects. In this context, we have shown previously that the cytidine analogue, gemcitabine, abolishes humoral responses but, in contrast, augments antigen-specific cellular antitumor immunity. This augmentation occurs in the context of increased antigen cross-presentation, T lymphocyte expansion, and infiltration of the tumor. Here, we combine an immunotherapy (CD40 ligation using FGK45; 100 micro g; i.p., q2dx3) with gemcitabine (120 microg/gram; i.p.; q3dx5) to treat established solid tumors. This protocol induced long-term cures in < or =80% of mice, and all of the cured mice were resistant to tumor rechallenge. Synergy between the drug and immunotherapy could not be established in vitro and was only seen in the context of tumor cell death. It was associated with an increase in both CD4 and CD8 T-cell infiltration of the tumor, but depletion studies clearly showed that CD4 T cells were not a necessary component of the cure. In contrast, CD8 T cells were absolutely required for the success of this treatment regimen. The priming effect of gemcitabine was not limited to debulking, because mice resected to an equivalent, or lesser residual tumor volume did not eradicate tumor with subsequent immunotherapy. This study provides evidence that chemotherapy has the capacity to augment cellular antitumor immunity, a finding with wider implications for the management of treatment-resistant solid tumors.
Nowak
Anna K
AK
University Department of Medicine, Western Australian Institute for Medical Research, Queen Elizabeth II Medical Centre, 4th Floor, G Block, Nedlands, Perth, Western Australia 6009.
Robinson
Bruce W S
BW
Lake
Richard A
RA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006388:Hemagglutinins / Q000096:biosynthesis / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008654:Mesothelioma / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D019013:CD40 Antigens; D006388:Hemagglutinins; D003841:Deoxycytidine; D000093542:Gemcitabine