The TNF-α/TNFR2 Pathway: Targeting a Brake to Release the Anti-tumor Immune Response

Abstract

Newly discovered anti-cancer immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cells, focus on spurring the anti-tumor effector T cell (Teff) response. Although such strategies have already demonstrated a sustained beneficial effect in certain malignancies, a substantial proportion of treated patients does not respond. CD4+FOXP3+ regulatory T cells (Tregs), a suppressive subset of T cells, can impair anti-tumor responses and reduce the efficacy of currently available immunotherapies. An alternative view that has emerged over the last decade proposes to tackle this immune brake by targeting the suppressive action of Tregs on the anti-tumoral response. It was recently demonstrated that the tumor necrosis factor alpha (TNF-α) tumor necrosis factor receptor 2 (TNFR2) is critical for the phenotypic stabilization and suppressive function of human and mouse Tregs. The broad non-specific effects of TNF-α infusion in patients initially led clinicians to abandon this signaling pathway as first-line therapy against neoplasms. Previously unrecognized, TNFR2 has emerged recently as a legitimate target for anti-cancer immune checkpoint therapy. Considering the accumulation of pre-clinical data on the role of TNFR2 and clinical reports of TNFR2+ Tregs and tumor cells in cancer patients, it is now clear that a TNFR2-centered approach could be a viable strategy, once again making the TNF-α pathway a promising anti-cancer target. Here, we review the role of the TNFR2 signaling pathway in tolerance and the equilibrium of T cell responses and its connections with oncogenesis. We analyze recent discoveries concerning the targeting of TNFR2 in cancer, as well as the advantages, limitations, and perspectives of such a strategy.

Downregulation of TNFR2 decreases survival gene expression, promotes apoptosis and affects the cell cycle of gastric cancer cells

“…Moreover, there was an increase in early apoptosis, with concomitant G1/S transition phase arrest (Figure 6C ). These results agree with those previously reported by our group in GC patient samples, in which we found upregulation of TNF/TNFR2 and cellular survival genes such as TRAF2 , CFLIP, and NFKB2 and downregulation of TNFR1 and CASP3 [ 14 ] , thus emphasizing the important role of TNFR2 in gastric carcinogenesis and TNFR2 silencing as a promising strategy for anticancer therapy[ 25 ].…”

“…TRAF2 recruits cIAP1 and cIAP2 after interaction with these receptors, thereby triggering nuclear translocation of NF-κB[ 30 ]. Therefore, TRAF2 is a negative regulator of TNF-induced apoptosis[ 30 ], and the use of this protein after TNFR2 activation results in TNFR1-induced apoptosis to the detriment of proliferation[ 25 ]. Therefore, a decrease in TRAF2 expression favours TNFR1-mediated apoptosis, contributing to the increase in the percentage of early apoptotic cells after TNFR2 downregulation.…”

TNFR2 Costimulation Differentially Impacts Regulatory and Conventional CD4+ T-Cell Metabolism

“…Whereas promoting TNFR2 activity on Tregs could be promising in autoimmune diseases and transplantation, TNFR2 inhibition is considered in cancer therapy (59). High TNFR2 expression is observed on certain cancers and on tumor-associated Tregs (59)(60)(61)(62)(63). TNFR2 agonism and antagonism are currently being explored in both autoimmune diseases and cancer, potentially opening new treatment avenues (62,(64)(65)(66).…”

TNFR2 costimulation differentially impacts regulatory and conventional CD4+ T-cell metabolism

“…High TNFR2 expression is observed on certain cancers and on tumor-associated Tregs (54)(55)(56)(57)(58).…”

“…Whereas promoting TNFR2 activity on Tregs could be promising in autoimmune diseases and transplantation, TNFR2 inhibition is considered in cancer therapy (54). High TNFR2 expression is observed on certain cancers and on tumor-associated Tregs (54-58). TNFR2 agonism and antagonism are currently being explored in both autoimmune diseases and cancer, potentially opening new treatment avenues (57, 59-61).…”