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Synergistic antitumor effects of CpG oligodeoxynucleotide and STAT3 inhibitory agent JSI‐124 in a mouse melanoma tumor model
Author(s) -
Molavi Ommoleila,
Ma Zengshuan,
Hamdy Samar,
Lai Raymond,
Lavasanifar Afsaneh,
Samuel John
Publication year - 2008
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2008.27
Subject(s) - stat3 , cancer research , melanoma , proinflammatory cytokine , cpg oligodeoxynucleotide , cd8 , stat protein , immunotherapy , pharmacology , chemistry , medicine , immunology , immune system , inflammation , phosphorylation , gene , biochemistry , gene expression , dna methylation
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 μg CpG, (c) 1 mg kg −1 JSI‐124 or (d) 10 μg 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, T H 1‐related cytokines (including IL‐12, IFN‐γ, TNF‐α 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‐β, 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.