Immunologic and therapeutic synergy of IL-27 and IL-2: enhancement of T cell sensitization, tumor-specific CTL reactivity and complete regression of disseminated neuroblastoma metastases in the liver and bone marrow.
IL-27 exerts antitumor activity in murine orthotopic neuroblastoma, but only partial antitumor effect in disseminated disease. This study demonstrates that combined treatment with IL-2 and IL-27 induces potent antitumor activity in disseminated neuroblastoma metastasis. Complete durable tumor regression was achieved in 90% of mice bearing metastatic TBJ-IL-27 tumors treated with IL-2 compared with only 40% of mice bearing TBJ-IL-27 tumors alone and 0% of mice bearing TBJ-FLAG tumors with or without IL-2 treatment. Comparable antitumor effects were achieved by IL-27 protein produced upon hydrodynamic IL-27 plasmid DNA delivery when combined with IL-2. Although delivery of IL-27 alone, or in combination with IL-2, mediated pronounced regression of neuroblastoma metastases in the liver, combined delivery of IL-27 and IL-2 was far more effective than IL-27 alone against bone marrow metastases. Combined exposure to IL-27 produced by tumor and IL-2 synergistically enhances the generation of tumor-specific CTL reactivity. Potentiation of CTL reactivity by IL-27 occurs via mechanisms that appear to be engaged during both the initial sensitization and effector phase. Potent immunologic memory responses are generated in mice cured of their disseminated disease by combined delivery of IL-27 and IL-2, and depletion of CD8(+) ablates the antitumor efficacy of this combination. Moreover, IL-27 delivery can inhibit the expansion of CD4(+)CD25(+)Foxp3(+) regulatory and IL-17-expressing CD4(+) cells that are otherwise observed among tumor-infiltrating lymphocytes from mice treated with IL-2. These studies demonstrate that IL-27 and IL-2 synergistically induce complete tumor regression and long-term survival in mice bearing widely metastatic neuroblastoma tumors.
Salcedo
Rosalba
R
Science Applications International Corporation, National Cancer Institute-Frederick, MD 21702, USA. lmirosi@ncifcrf.gov
Hixon
Julie A
JA
Stauffer
Jimmy K
JK
Jalah
Rashmi
R
Brooks
Alan D
AD
Khan
Tahira
T
Dai
Ren-Ming
RM
Scheetz
Loretta
L
Lincoln
Erin
E
Back
Timothy C
TC
Powell
Douglas
D
Hurwitz
Arthur A
AA
Sayers
Thomas J
TJ
Kastelein
Robert
R
Pavlakis
George N
GN
Felber
Barbara K
BK
Trinchieri
Giorgio
G
Wigginton
Jon M
JM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology* / Q000494:pharmacology; D019046:Bone Marrow Neoplasms / Q000188:drug therapy / Q000556:secondary; D004357:Drug Synergism; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology*; D007378:Interleukins / Q000008:administration & dosage / Q000276:immunology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy / Q000276:immunology* / Q000556:secondary; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
C486767:Il27 protein, mouse; D007376:Interleukin-2; D007378:Interleukins; D007371:Interferon-gamma