Editorial: The role of TNF-TNFR2 signal in immunosuppressive cells and its therapeutic implications, volume II

analyzed the correlation of levels of soluble TNFR2 (sTNFR2) in the blood and the risk of cancer. The results show that the levels of sTNFR2 were markedly enhanced in circulation of patients with spectrum of cancers, including colorectal cancer, ovarian cancer, breast cancer, non-Hodgkin ’ s lymphoma, Hodgkin ’ s lymphoma, lung cancer, hepatocarcinoma, and glioblastoma. A random-effect meta-analysis shows that the cancer-speci ﬁ c odds ratio (OR) signi ﬁ cantly correlated between the elevated levels of circulating sTNFR2 and the risk of colorectal cancer, non-Hodgkin ’ s lymphoma, and hepatocarcinoma.


Introduction
There is compelling evidence that TNFR2 signaling plays a decisive role in the activation, expansion, function and phenotypical stability of CD4 + Foxp3 + regulatory T cells (Tregs) (1)(2)(3)(4). Current research focuses on the translation of this property of TNFR2 into novel treatment for major human diseases, while the molecular basis underlying Tregstimulatory effect of TNFR2 is also actively pursued. This Research Topic showcases the latest experimental studies as well as expert perspectives incorporating recent findings in the literature.

Inhibition of TNFR2 signaling for cancer immunotherapy
Chen, Y. et al. from Adlai Nortye USA Inc. reported that a humanized antagonistic antibody, AN3025, at sub-nanomolar affinity binds to the extracellular domain of human TNFR2. In vitro treatment with AN3025 inhibited the immunosuppressive effect of human Tregs (hTregs), resulting in an enhanced proliferation and IFNg production by co-cultured effector T cells (Teffs). In TNFR2 humanized mice, AN3025 treatment markedly inhibited the growth of MC38 tumor, accompanied by the reduction of tumor-infiltrating Tregs and an increase in the number of effector CD4 and CD8 T cells in the tumor. Further, the in vivo anti-tumor effect of AN3025 could be enhanced when used together with anti-PD-L1 antibody. Thus, this antagonistic anti-TNFR2 antibody may be used as a monotherapy or combined with other immune therapeutics in the treatment of cancer (

Levels of soluble TNFR2 in the circulation as a cancer diagnostic biomarker
Based on the previously published data, Kartikasari et al. from RMIT University analyzed the correlation of levels of soluble TNFR2 (sTNFR2) in the blood and the risk of cancer. The results show that the levels of sTNFR2 were markedly enhanced in circulation of patients with spectrum of cancers, including colorectal cancer, ovarian cancer, breast cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer, hepatocarcinoma, and glioblastoma. A random-effect meta-analysis shows that the cancer-specific odds ratio (OR) significantly correlated between the elevated levels of circulating sTNFR2 and the risk of colorectal cancer, non-Hodgkin's lymphoma, and hepatocarcinoma. Consistent with the notion that TNFR2 promotes the development of cancer, this study for the first time provides clear evidence that sTNFR2 in the circulation may be used as a diagnostic biomarker for certain types of cancers (Kartikasari et al.).

Activation of TNFR2 signaling for the treatment of inflammatory diseases
Previously, it was shown that the clinical effect of anti-TNF antibody (adalimumab) on rheumatoid arthritis is at least partially mediated by the elevated levels of transmembrane bound TNF expression on monocytes and the expansion of Tregs through TNFR2 signaling (5). This may represent a common mechanism of some anti-inflammatory or immunosuppressive therapeutics. Since tetrandrine (TET), a small molecular compound isolated from Chinese herb medicine, was found to have similar effect as adalimumab (6). Chen

Differential responses of Tregs and
Teffs to TNFR2 co-stimulation at transcriptomic and metabolic levels TNFR2 can be expressed by the activated T effector cells (7). Mensink et al. from Leiden University showed differential responses of human Tconvs (CD4 + conventional T cells) and tTreg (thymus derived Tregs) to TNFR2 co-stimulation at the transcriptomic and metabolic levels. Their results showed that both activated human Tconvs and tTregs could respond to TNFR2 stimulation, but in a different fashion, with the breadth of the transcriptomic changes much larger in tTregs. This suggests a greater impact of TNFR2 costimulation on the transcriptome of tTregs versus that of Tconvs. TNFR2 could also play a role in the metabolism of both tTregs and Tconvs. Its signal could remodel glutamine metabolism in both cell types. However, TNFR2 only enhanced glycolysis and TCA cycle in tTreg (Mensink et al.).
Taken together, the 9 publications in this Research Topic include translational research, mechanistic studies, meta-analysis and literature analysis. They showcase major directions and aim to help the research community to understand current progress in this rapidly growing field. Currently, a number of TNFR2-targeting antibodies are under clinical investigation, including those with both antagonistic or agonistic properties. The publications in this Research Topic also help set up the context to understand the clinical trial results which are expected to become available in the near future.

Author contributions
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.