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.
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.
Chapoval
A I
AI
The Jackson Laboratory, Bar Harbor, ME 04609, USA. chapoval.andrei@mayo.edu
Fuller
J A
JA
Kremlev
S G
SG
Kamdar
S J
SJ
Evans
R
R
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic; D004354:Drug Screening Assays, Antitumor; D006183:H-2 Antigens / Q000276:immunology; D018960:Hyaluronan Receptors / Q000032:analysis; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000235:genetics / Q000276:immunology; D007155:Immunologic Factors / Q000627:therapeutic use*; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000627:therapeutic use*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000556:secondary* / Q000628:therapy*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000276:immunology / Q000556:secondary* / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D018906:Antineoplastic Agents, Alkylating; D006183:H-2 Antigens; D018960:Hyaluronan Receptors; D007155:Immunologic Factors; D019409:Interleukin-15; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D003520:Cyclophosphamide