Interleukin-21 triggers both cellular and humoral immune responses leading to therapeutic antitumor effects against head and neck squamous cell carcinoma.
BACKGROUND
Interleukin-21 (IL-21) plays important roles in the regulation of T, B, and natural killer (NK) cells. We hypothesized that the cytokine may provide a novel immunotherapy strategy for cancer by stimulating both Th1 and Th2 immune responses. In this context, antitumor immunity induced by IL-21 was examined in mice bearing subcutaneous head and neck squamous cell carcinomas (HNSCC).


METHODS
A plasmid vector encoding murine IL-21 was injected intravenously into mice with pre-established HNSCC tumors, either alone or in combination with a vector construct expressing IL-15. Cytotoxic T lymphocyte (CTL) and NK killing activities were evaluated by chrome release assays, while HNSCC-specific antibody was examined by flow cytometry and ELISA.


RESULTS
Significant antitumor effects were obtained by repeated transfection with either the IL-21 or the IL-15 gene. Co-administration of both cytokine genes resulted in increased suppression of tumor growth, significantly prolonging the survival periods of the animals. Thirty percent of the tumor-bearing mice that received the combination therapy survived for more than 300 days, completely rejecting rechallenge with the tumor at a distant site. IL-21 induced significant elevation of HNSCC-specific CTL activity, while IL-21 and IL-15 augmented NK activity in an additive manner. IL-21 gene transfer also promoted the production of tumor-specific IgG.


CONCLUSIONS
In vivo transduction of the IL-21 gene elicits powerful antitumor immunity, including both humoral and cellular arms of the immune response, and results in significant suppression of pre-established HNSCC. Co-transfer of the IL-15 gene further improved the therapeutic outcome, mainly by augmenting NK tumoricidal activity. The biological effects of IL-21 may be in sharp contrast to those of conventional Th1 and Th2 cytokines, suggesting intriguing implications of this cytokine for the classical concept of Th1 vs. Th2 paradigm.
Nakano
Hiroshi
H
Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Kishida
Tsunao
T
Asada
Hidetsugu
H
Shin-Ya
Masaharu
M
Shinomiya
Takashi
T
Imanishi
Jiro
J
Shimada
Taketoshi
T
Nakai
Shigeru
S
Takeuchi
Minoru
M
Hisa
Yasuo
Y
Mazda
Osam
O
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000378:metabolism / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000628:therapy*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007378:Interleukins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D000098546:Interleukin-21
D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D019409:Interleukin-15; D007378:Interleukins; D000098546:Interleukin-21