Synergistic antitumor effects of CpG oligodeoxynucleotide and STAT3 inhibitory agent JSI-124 in a mouse melanoma tumor model.
One of the major limitations for cancer immunotherapy is related to the frequent existence of an intra-tumoral immunosuppressive environment, to which STAT3 (Signal transducer and activator of transcription-3) activation in tumor and dendritic cells (DCs) are believed to contribute. In this study, we tested the hypothesis that the combination of CpG (a DC activator) and JSI-124 (a STAT3 inhibitor) may generate synergistic antitumor effects compared to CpG or JSI-124 alone. B16-F10, a mouse melanoma cell line that has constitutively active STAT3, was grafted in C57BL/6 mice and then tumor-bearing mice treated intra-tumorally with (a) phosphate buffered saline, (b) 10 microg CpG, (c) 1 mg kg(-1) JSI-124 or (d) 10 microg CpG+1 mg kg(-1) JSI-124. The effects of treatments on tumor growth, survival and antitumor immune responses were evaluated. Although significant antitumor effects were detected with the single-agent treatments, the CpG+JSI-124 treatment resulted in synergistic antitumor effects compared to CpG or JSI-124 alone. Correlating with these findings, the combination therapy resulted in significantly higher intra-tumoral levels of several proinflammatory, TH1-related cytokines (including IL-12, IFN-gamma, TNF-alpha and IL-2), increases in intra-tumoral CD8+ and CD4+ T cells expressing activation/memory markers and NK cells and increases in activated DCs in the tumors and regional lymph nodes (LNs). Concomitantly, the combination therapy led to a significantly decreased level of immunosuppression, as evidenced by lower intra-tumoral level of VEGF and TGF-beta, and decreased number of CD4+CD25+Foxp3+ regulatory T cells in the regional LNs. This study has provided the proof-of-principle for combining CpG and JSI-124 to enhance antitumor immune responses.
Molavi
Ommoleila
O
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Ma
Zengshuan
Z
Hamdy
Samar
S
Lai
Raymond
R
Lavasanifar
Afsaneh
A
Samuel
John
J
D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014315:Triterpenes / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C408982:CPG-oligonucleotide; D007376:Interleukin-2; D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; C038106:cucurbitacin I