TNFR2: Role in Cancer Immunology and Immunotherapy

Abstract

Immune checkpoint inhibitors (ICIs), including anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD-1/PD-L1 (programmed death-1/programmed death-ligand 1), represent a turning point in the cancer immunotherapy. However, only a minor fraction of patients could derive benefit from such therapy. Therefore, new strategies targeting additional immune regulatory mechanisms are urgently needed. CD4 + Foxp3 + regulatory T cells (Tregs) represent a major cellular mechanism in cancer immune evasion. There is compelling evidence that tumor necrosis factor (TNF) receptor type II (TNFR2) plays a decisive role in the activation and expansion of Tregs and other types of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs). Furthermore, TNFR2 is also expressed by some tumor cells. Emerging experimental evidence indicates that TNFR2 may be a therapeutic target to enhance naturally occurring or immunotherapeutic-triggered anti-tumor immune responses. In this article, we discuss recent advances in the understanding of the mechanistic basis underlying the Treg-boosting effect of TNFR2. The role of TNFR2-expressing highly suppressive Tregs in tumor immune evasion and their possible contribution to the non-responsiveness to checkpoint treatment are analyzed. Moreover, the role of TNFR2 expression on tumor cells and the impact of TNFR2 signaling on other types of cells that shape the immunological landscape in the tumor microenvironment, such as MDSCs, MSCs, ECs, EPCs, CD8 + CTLs, and NK cells, are also discussed. The reports revealing the effect of TNFR2-targeting pharmacological agents in the experimental cancer immunotherapy are summarized. We also discuss the potential opportunities and challenges for TNFR2-targeting immunotherapy.

TNFα and Immune Checkpoint Inhibition: Friend or Foe for Lung Cancer?

“…Thus, instead of creating an antitumor immune response, increased AT-II cell-specific MHC-II expression can trigger Treg differentiation [104]. Numerous studies evaluated TNFR2 as a potential biomarker for NSCLC as it has been shown to be crucial for TNFα-mediated immunosuppression [105,106]. High amounts of TNFR2 + Tregs have been found in the TME of murine [39,107] as well as human advanced lung cancers [108,109], suggesting that Tregs are activated through TNFα/TNFR2 signaling.…”

Targeting TNFR2 in Cancer: All Roads Lead to Rome

“…TNFR2 plays a vital role in the function maintenance of NK cells. NK cells play a central role in the antitumor process in TME ( 2 ), acting directly through cell-mediated cytotoxicity and by secreting cytokines. Activation of the TNF/TNFR2 pathway enhances NK cell cytotoxicity, and TNFα also enhanced murine NK cell IFNγ production via TNFR2 in vivo and in vitro ( 72 ).…”

“…Improved biomarkers may help to better select patients who are more likely to respond to immunotherapy and benefit new drug development. TNF receptor 2 (TNFR2) has become one of the best potential immune molecules that might be targeted mainly because of its vital role in tumor microenvironments (TMEs) ( 2 ).…”

Antagonistic Antibody Targeting TNFR2 Inhibits Regulatory T Cell Function to Promote Anti-Tumor Activity

“…Programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) checkpoint inhibitors are important milestones in the drug development for cancer therapy ( 1 ). Even though ICIs have demonstrated successful elicitation of anti-tumor activity in multiple cancer types ( 2 ), the percentage of cancer patients who can respond to ICIs treatments is still limited ( 3 ). The combination of a checkpoint inhibitor with chemotherapy or with another checkpoint inhibitor could further improve the efficacy and response rates ( 4 , 5 ).…”

“…Overall, TNFR2 is emerging as an attractive target for cancer treatment. TNFR2 antagonistic antibody appears to be a promising approach to inhibit Tregs function in tumor patients and to induce anti-tumor immune response ( 2 , 29 ). In this study, we characterized AN3025, a humanized antibody against human TNFR2 (hTNFR2), in aspect of binding affinity, species cross reactivity and capacity to block TNFR2 activation.…”