TY - JOUR
T1 - Combination chemotherapy and IL-15 administration induce permanent tumor regression in a mouse lung tumor model
T2 - NK and T cell-mediated effects antagonized by B cells
AU - Chapoval, Andrei I.
AU - Fuller, Jane A.
AU - Kremlev, Sergey G.
AU - Kamdar, Sonya J.
AU - Evans, Robert
PY - 1998/12/15
Y1 - 1998/12/15
N2 - 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.
AB - 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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M3 - Article
C2 - 9862733
AN - SCOPUS:0032534579
SN - 0022-1767
VL - 161
SP - 6977
EP - 6984
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -