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.

通过II型肿瘤坏死因子（TNF）受体（TNFR2），TNF优先激活，扩展和促进CD4 ⁺ Foxp3 ⁺调节性T（T _reg）细胞的表型稳定性。具有高TNFR2含量的那些T _reg细胞具有最大的免疫抑制能力。我们调查了靶向TNFR2是否可以有效抑制T _reg的活性细胞，因此增强了癌症免疫疗法的功效。我们发现，相对于次优剂量的免疫刺激性Toll样受体9配体CpG寡脱氧核苷酸（ODN），次优剂量的CpG ODN与阻断TNFR2的抗体M861的结合能更明显地抑制皮下移植小鼠CT26的生长结肠肿瘤细胞。这导致TNFR2 ⁺ T _reg细胞明显减少，干扰素-γ阳性（IFN-γ ⁺）CD8 ⁺增多。细胞毒性T淋巴细胞浸润肿瘤，并改善了小鼠队列的长期无瘤生存率。无肿瘤小鼠对相同但非无关的（4T1乳腺癌）细胞具有抵抗再攻击的能力。TNFR2阻断抗体和CD25靶向抗体的组合治疗还导致在同系4T1乳腺癌小鼠模型中肿瘤生长的抑制作用增强。因此，TNFR2抑制剂和免疫治疗刺激剂的组合可以代表针对各种癌症的更有效的治疗策略。