TNFR2 antagonistic antibody induces the death of tumor infiltrating CD4+Foxp3+ regulatory T cells

• Published in: Cellular oncology (Dordrecht) 2023-02, Vol.46 (1), p.167-177
• Main Authors: He, Tianzhen, Chen, Yibo, Yang, De, Islam, Md Sahidul, Chou, Chon-Kit, Liu, Jiarui, Faustman, Denise L., Oppenheim, Joost J., Chen, Xin
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antitumor activity; Biomedical and Life Sciences; Biomedicine; Cancer immunotherapy; Cancer Research; CD4 antigen; Cell death; Dexamethasone; Forkhead Transcription Factors - metabolism; Foxp3 protein; Immunoregulation; Lymph nodes; Lymphocytes T; Lymphoma; Mice; Neoplasms - metabolism; Oncology; Original Article; Pathology; Receptors, Tumor Necrosis Factor, Type II - metabolism; T-Lymphocytes, Regulatory - metabolism; Tumor necrosis factor; Viability
• ISSN: 2211-3428; 2211-3436
• DOI: 10.1007/s13402-022-00742-0

Background TNFR2 expression is a characteristic of highly potent immunosuppressive tumor infiltrating CD4 + Foxp3 + regulatory T cells (Tregs). There is compelling evidence that TNF through TNFR2 preferentially stimulates the activation and expansion of Tregs. We and others, therefore, proposed that targeting TNFR2 may provide a novel strategy in cancer immunotherapy. Several studies have shown the effect of TNFR2 antagonistic antibodies in different tumor models. However, the exact action of the TNFR2 antibody on Tregs remained understood. Method TY101, an anti-murine TNFR2 antibody, was used to examine the effect of TNFR2 blockade on Treg proliferation and viability in vitro. The role of TNFR2 on Treg viability was further validated by TNFR2 knockout mice and in the TY101 antagonistic antibody-treated mouse tumor model. Results In this study, we found that an anti-mouse TNFR2 antibody TY101 could inhibit TNF-induced proliferative expansion of Tregs, indicative of an antagonistic property. To examine the effect of TY101 antagonistic antibody on Treg viability, we treated unfractionated lymph node (L.N.) cells with Dexamethasone (Dex) which was known to induce T cell death. The result showed that TY101 antagonistic antibody treatment further promoted Treg death in the presence of Dex. This led us to find that TNFR2 expression was crucial for the survival of Tregs. In the mouse EG7 lymphoma model, treatment with TY101 antagonistic antibody potently inhibited tumor growth, resulting in complete regression of the tumor in 60% of mice. The treatment with TY101 antagonistic antibody elicited potent antitumor immune responses in this model, accompanied by enhanced death of Tregs. Conclusion This study, therefore, provides clear experimental evidence that TNFR2 antagonistic antibody, TY101, can promote the death of Tregs, and this effect may be attributable to the antitumor effect of TNFR2 antagonistic antibody.