Blockade of TNFR2 signaling enhances the immunotherapeutic effect of CpG ODN in a mouse model of colon cancer

Yingjie Nie, Jiang He, Hidekazu Shirota, Anna L. Trivett, De Yang, Dennis M. Klinman, Joost J. Oppenheim, Xin Chen

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Through the tumor necrosis factor (TNF) receptor type II (TNFR2), TNF preferentially activates, expands, and promotes the phenotypic stability of CD4 + Foxp3 + regulatory T (T reg ) cells. Those T reg cells that have a high abundance of TNFR2 have the maximal immunosuppressive capacity. We investigated whether targeting TNFR2 could effectively suppress the activity of T reg cells and consequently enhance the efficacy of cancer immunotherapy. We found that, relative to a suboptimal dose of the immunostimulatory Toll-like receptor 9 ligand CpG oligodeoxynucleotide (ODN), the combination of the suboptimal dose of CpG ODN with the TNFR2-blocking antibody M861 more markedly inhibited the growth of subcutaneously grafted mouse CT26 colon tumor cells. This resulted in markedly fewer TNFR2 + T reg cells and more interferon-γ-positive (IFN-γ + ) CD8 + cytotoxic T lymphocytes infiltrating the tumor and improved long-term tumor-free survival in the mouse cohort. Tumor-free mice were resistant to rechallenge by the same but not unrelated (4T1 breast cancer) cells. Treatment with the combination of TNFR2-blocking antibody and a CD25-targeted antibody also resulted in enhanced inhibition of tumor growth in a syngeneic 4T1 mouse model of breast cancer. Thus, the combination of a TNFR2 inhibitor and an immunotherapeutic stimulant may represent a more effective treatment strategy for various cancers.

Original languageEnglish
Article numbereaan0790
JournalScience Signaling
Volume11
Issue number511
DOIs
Publication statusPublished - 2018 Jan 2
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Nie, Y., He, J., Shirota, H., Trivett, A. L., Yang, D., Klinman, D. M., Oppenheim, J. J., & Chen, X. (2018). Blockade of TNFR2 signaling enhances the immunotherapeutic effect of CpG ODN in a mouse model of colon cancer. Science Signaling, 11(511), [eaan0790]. https://doi.org/10.1126/scisignal.aan0790