IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors: role for CD8+ T cells.
We have shown previously that IFN-gamma-inducing cytokines such as IL-12 can mediate potent antitumor effects against murine solid tumors. IL-27 is a newly described IL-12-related cytokine that potentiates various aspects of T and/or NK cell function. We hypothesized that IL-27 might also mediate potent antitumor activity in vivo. TBJ neuroblastoma cells engineered to overexpress IL-27 demonstrated markedly delayed growth compared with control mice, and complete durable tumor regression was observed in >90% of mice bearing either s.c. or orthotopic intra-adrenal tumors, and 40% of mice bearing induced metastatic disease. The majority of mice cured of their original TBJ-IL-27 tumors were resistant to tumor rechallenge. Furthermore, TBJ-IL-27 tumors were heavily infiltrated by CD8(+) T cells, and draining lymph node-derived lymphocytes from mice bearing s.c. TBJ-IL-27 tumors are primed to proliferate more readily when cultured ex vivo with anti-CD3/anti-CD28 compared with lymphocytes from mice bearing control tumors, and to secrete higher levels of IFN-gamma. In addition, marked enhancement of local IFN-gamma gene expression and potent up-regulation of cell surface MHC class I expression are noted within TBJ-IL-27 tumors compared with control tumors. Functionally, these alterations occur in conjunction with the generation of tumor-specific CTL reactivity in mice bearing TBJ-IL-27 tumors, and the induction of tumor regression via mechanisms that are critically dependent on CD8(+), but not CD4(+) T cells or NK cells. Collectively, these studies suggest that IL-27 could be used therapeutically to potentiate the host antitumor immune response in patients with malignancy.
Salcedo
Rosalba
R
Pediatric Oncology Branch, National Cancer Institute-Center for Cancer Research, Frederick, MD 21702, USA.
Stauffer
Jimmy K
JK
Lincoln
Erin
E
Back
Timothy C
TC
Hixon
Julie A
JA
Hahn
Cynthia
C
Shafer-Weaver
Kimberly
K
Malyguine
Anatoli
A
Kastelein
Robert
R
Wigginton
Jon M
JM
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D007156:Immunologic Memory; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation / Q000276:immunology; D009447:Neuroblastoma / Q000235:genetics / Q000276:immunology / Q000556:secondary* / Q000628:therapy*; D014162:Transfection; D015854:Up-Regulation / Q000276:immunology
D000276:Adjuvants, Immunologic; D015395:Histocompatibility Antigens Class I; C486767:Il27 protein, mouse; D007378:Interleukins; D007371:Interferon-gamma