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.

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

• Authors: A I Chapoval, J A Fuller, S G Kremlev, S J Kamdar, R Evans
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 161 Issue 12 Pg. 6977-84 (Dec 15 1998) ISSN: 0022-1767 [Print] United States
• PMID: 9862733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents, Alkylating
• H-2 Antigens
• Hyaluronan Receptors
• Immunologic Factors
• Interleukin-15
• Receptors, Antigen, T-Cell, alpha-beta
• Receptors, Antigen, T-Cell, gamma-delta
• Cyclophosphamide

Topics

• Animals
• Antineoplastic Agents, Alkylating (therapeutic use)
• B-Lymphocytes (immunology)
• Combined Modality Therapy
• Cyclophosphamide (therapeutic use)
• Cytotoxicity, Immunologic
• Drug Screening Assays, Antitumor
• H-2 Antigens (immunology)
• Hyaluronan Receptors (analysis)
• Immunologic Deficiency Syndromes (complications, genetics, immunology)
• Immunologic Factors (therapeutic use)
• Immunologic Memory
• Interleukin-15 (therapeutic use)
• Killer Cells, Lymphokine-Activated (immunology)
• Killer Cells, Natural (immunology)
• Lung Neoplasms (drug therapy, immunology, secondary, therapy)
• Lymphocyte Activation
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Mutant Strains
• Mice, Nude
• Mice, SCID
• Neoplasm Transplantation
• Receptors, Antigen, T-Cell, alpha-beta (deficiency, genetics)
• Receptors, Antigen, T-Cell, gamma-delta (deficiency, genetics)
• Rhabdomyosarcoma (drug therapy, immunology, secondary, therapy)
• T-Lymphocyte Subsets (immunology)