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*CYCLOPHOSPHAMIDE
Medline Plus Health Information
*Lung Cancer
The Journal of Immunology, 1998, 161: 6977-6984.
Copyright © 1998 by The American Association of Immunologists

Combination Chemotherapy and IL-15 Administration Induce Permanent Tumor Regression in a Mouse Lung Tumor Model: NK and T Cell-Mediated Effects Antagonized by B Cells1

Andrei I. Chapoval2, Jane A. Fuller, Sergey G. Kremlev, Sonya J. Kamdar and Robert Evans

The Jackson Laboratory, Bar Harbor, ME 04609

Previous studies have demonstrated that IL-15 administration after cyclophosphamide (CY) injection of C57BL/6J mice bearing the i.m. 76-9 rhabdomyosarcoma resulted in a significant prolongation of life. In the present study, we investigated the immune response against the 76-9 experimental lung metastases after CY + IL-15 therapy. Administration of CY + IL-15, but not IL-15 alone, induced prolongation of life and cures in 32% of mice bearing established experimental pulmonary metastases of 76-9 tumor. The CY + IL-15 therapy resulted in increased levels of NK1.1+/LGL-1+ cells, and CD8+/CD44+ T cells in PBL. In vitro cytotoxic assay of PBL indicated the induction of lymphokine-activated killer cell activity, but no evident tumor-specific class I-restricted lytic activity. Survival studies showed that the presence of NK and T lymphocytes is necessary for successful CY + IL-15 therapy. Experiments using knockout mice implied that either {alpha}ß or {gamma}{delta} T cells were required for an antitumor effect induced by CY + IL-15 therapy. However, mice lacking in both {alpha}ß and {gamma}{delta} T cells failed to respond to combination therapy. Cured B6 and {alpha}ß or {gamma}{delta} T cell-deficient mice were immune to rechallenge with 76-9, but not B16LM tumor. B cell-deficient mice showed a significant improvement in the survival rate both after CY and combination CY + IL-15 therapy compared with normal B6 mice. Overall, the data suggest that the interaction of NK cells with tumor-specific {alpha}ß or {gamma}{delta} T lymphocytes is necessary for successful therapy, while B cells appear to suppress the antitumor effects of CY + IL-15 therapy.




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