Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy.
Most cytotoxic drugs have gross effects on the immune system, such as neutropenia and lymphopenia. However, their effects on tumor-specific immune responses are unknown. Gemcitabine is a nucleoside analogue that is frequently used to treat non-small cell lung cancer. It is also active in other malignancies, either alone or in combination with cisplatin. Here, we investigate its effects on antigen-specific antitumor immunity using a murine tumor cell line transfected to express influenza virus hemagglutinin (HA). CD4(+), CD8(+), and B220(+) lymphocyte numbers all decreased during chemotherapy (120 microg/g, i.p., every third day for five doses), but B cells were selectively depleted. Gemcitabine induced a profound suppression of the IgG antibody response to HA, and this was unrelated to tumor size. In contrast, in vitro T-lymphocyte recall responses to the class I- and class II-restricted dominant peptide epitopes of HA were enhanced in tumor-bearing, gemcitabine-treated mice. We found that gemcitabine was >2-fold more potent in its ability to inhibit B-lymphocyte proliferation compared with T-lymphocyte proliferation. Thus, gemcitabine does not appear to be detrimental to specific antitumor cellular immunity and may be useful in combination chemo-immunotherapy protocols. In contrast, vaccination protocols requiring a humoral immune response for maximal efficacy may be compromised in patients treated with gemcitabine.
Nowak
Anna K
AK
Western Australian Institute for Medical Research, University Department of Medicine, 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; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D000093542:Gemcitabine
D000912:Antibodies, Neoplasm; D000964:Antimetabolites, Antineoplastic; D018985:Epitopes, B-Lymphocyte; D007166:Immunosuppressive Agents; D003841:Deoxycytidine; D000093542:Gemcitabine