Table 1.
Different TNFR2 targeted therapies and their mechanisms of action
| Targeted therapy | Molecular target (TNFR2 or downstream) | Mechanism of action | Cancer type (Tumor model) |
Status (Animal or Clinical) | Ref |
|---|---|---|---|---|---|
| Cyclophosphamide | CD4+CD25+TNFR2+T-regs | Activate CD8+ T cells | Mesothelioma | mouse model | [309] |
| 2 TNFR2 antagonistic antibodies | RelB, TRAF2, TRAF3, cIAP2/BIRC3, MAP3K11, CHUK, NFKBIA, and NFKBIE | Inhibit Treg proliferation, reduce soluble TNFR2 secretion from normal cells, and enable T effector cell expansion. Inhibit RelA/NF-κB phosphorylation | Ovarian cancer | Cells (ovcar3) | [311] |
| M861 anti-TNFR2 antibody | TNFR2+ T-reg cells |
Inhibit interaction between TNF-α and TNFR2 Decrease trans-membrane TNFR2 levels and inhibit the expansion and proliferation of T-regs |
Colon cancer | Mouse model | [196] |
| M861 and the toll-like receptor 9 ligand CpG oligodeoxynucleotide (CpG-ODN) | TNFR2+ T-reg cells |
Reduce surface TNFR2 levels Decrease T-reg cell count Increase CD8+ T cell count, release IFN-γ |
Colon cancer | Mouse model | [196] |
| CpG-ODN | DCs, B cells, and CTLs |
Diminish immunosuppressive function of MDSCs Produce substantial amounts of TNF-α, activate and expand T-regs through TNFR2 |
Colon cancer | Mouse model | [196] |
| Y7, Y9 and Y10 | Bind epitopes in CRD1 to CRD4 | Overlap with the ligand interface to effectively block TNF-α | Colon cancer, breast cancer, fibrosarcoma, B lymphocyte sarcoma, melanoma | Mouse model | [313] |
| TNFR2 IgG2 antibodies | T-reg cells | TME-directed killing specificity | T cell lymphoma | Patients and cell lines | [314] |
| anti-TNFR2 (TY101) antibodies and anti-PD-1 (CD279) |
TNFR2+T-regs CD8+ T cells |
Reduce the number of TNFR2+T-regs Increase the ratio of CD8+ T cells |
Colon cancer | Murine colon cancer models of ct26 and mc38 | [304] |
| TY101, CD120b | nucleosome binding proteins 1 (HMGN-1, TLR-4 agonist) and R848 or 3 M-052 (TLR-7/8 agonists) |
Deplete Tregs and stimulate cytotoxic CD8 T cell activation |
Colon cancer | Murine colon cancer | [306, 307] |
| scutellarin |
TNFR2 on both tumor and T-reg cells, prevent the binding of TNF-α to TNFR2 |
Inhibit p-38 MAPK phosphorylation | Colon cancer | Mouse ct26 colon cancer model | [308] |
| anti-PDL-1 and anti-PD-1 | NF-κB-p65pathway | Inhibit growth, relieve tumor immunosuppression, and generate robust memory recall | Pancreatic ductal adenocarcinoma (PDAC) and colon cancer | Mouse models | [175, 304] |
| Ab-1 and Ab-2 anti-TNFR2 antibodies combined with nivolumab (anti-PD-1) | CRD1 | Inhibit CD4+ T cells and CD8+ T cells | Breast cancer | Mouse model of MDA-MB-231-established BC | [313] |
| anti-TNFR2 | IL-17A, CXCL-10, IFN-γ, TGF-1β, IL-10, TNF-α, and TNFR2 |
Inhibit CD4+CD25+TNFR2+T-regs proliferation Reduce FoxP3 expression Reduce inhibitory effect and increase the proportion of CD8+ T cells |
Breast cancer | Mice model | [8] |
T-regs, T-regulatory cells; TRAF2, TNF receptor associated factor 2; TRAF3, TNF receptor associated factor 3; cIAP2, cellular inhibitor of apoptosis 2; BIRC3, baculoviral IAP repeat containing 3; MAP3K11, mitogen-activated protein kinase kinase kinase 11; TGF-1β, transforming growth factor beta; IL-10, interleukin 10; IL-17A, interleukin 17 alpha; CXCL-10, C-X-C motif chemokine ligand 10; IFN-γ, interferon gamma; CRD, cysteine-rich domain; DC, dendritic cell; CTLs, cytotoxicity T lymphocyte; TNF-α; tumor necrosis alpha; TNFR2, tumor necrosis receptor type two; TME, tumor microenvironment; PD-1, programmed death 1; PD-L1, programmed death ligand 1