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 cells

Andrei Chapoval, Jane A. Fuller, Sergey G. Kremlev, Sonya J. Kamdar, Robert Evans

Research output: Contribution to journalArticle

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Abstract

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 αβ or γδ T cells were required for an antitumor effect induced by CY + IL-15 therapy. However, mice lacking in both αβ and γδ T cells failed to respond to combination therapy. Cured B6 and αβ or γδ 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 αβ or γδ T lymphocytes is necessary for successful therapy, while B cells appear to suppress the antitumor effects of CY + IL-15 therapy.

Original languageEnglish (US)
Pages (from-to)6977-6984
Number of pages8
JournalJournal of Immunology
Volume161
Issue number12
StatePublished - Dec 15 1998
Externally publishedYes

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Interleukin-15
Combination Drug Therapy
Natural Killer Cells
Cyclophosphamide
B-Lymphocytes
T-Lymphocytes
Lung
Neoplasms
Life Support Care
Therapeutics
Neoplasm Metastasis
Lymphokine-Activated Killer Cells
Rhabdomyosarcoma
Inbred C57BL Mouse
Knockout Mice
Injections

ASJC Scopus subject areas

  • Immunology

Cite this

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 cells. / Chapoval, Andrei; Fuller, Jane A.; Kremlev, Sergey G.; Kamdar, Sonya J.; Evans, Robert.

In: Journal of Immunology, Vol. 161, No. 12, 15.12.1998, p. 6977-6984.

Research output: Contribution to journalArticle

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abstract = "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 αβ or γδ T cells were required for an antitumor effect induced by CY + IL-15 therapy. However, mice lacking in both αβ and γδ T cells failed to respond to combination therapy. Cured B6 and αβ or γδ 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 αβ or γδ 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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