Research ArticleCancer Immunotherapy

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

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Sci. Signal.  02 Jan 2018:
Vol. 11, Issue 511, eaan0790
DOI: 10.1126/scisignal.aan0790

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Taking aim at regulatory T cells

Cancer immunotherapy attempts to stimulate the patient’s own immune system against a tumor, but despite its potential, the clinical efficacy of immunotherapy has been extremely limited. In some cases, the patient’s own immune system can counteract those efforts, such as through T cell exhaustion or the action of naturally suppressive regulatory T (Treg) cells. Nie et al. show that co-inhibiting a receptor for tumor necrosis factor (TNF) reduced Treg cell activity and proliferation, stimulated antitumor immune memory, and slowed the growth of—or even shrank—colon and breast tumors in mice that were unresponsive to common single-agent immunotherapies. The findings suggest that the addition of anti-TNF therapeutics may help increase and broaden the efficacy of immunotherapy for cancer patients.

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 (Treg) cells. Those Treg cells that have a high abundance of TNFR2 have the maximal immunosuppressive capacity. We investigated whether targeting TNFR2 could effectively suppress the activity of Treg 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+ Treg 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.

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