ImmunoTargets and Therapy (Apr 2021)
TNFR2: Role in Cancer Immunology and Immunotherapy
Abstract
Yang Yang, Md Sahidul Islam, Yuanjia Hu, Xin Chen State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, 999078, People’s Republic of ChinaCorrespondence: Xin ChenState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, 999078, People’s Republic of ChinaTel +853 8822 4513Fax +853 2884 1358Email [email protected]: 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.Keywords: TNF, TNFR2, cancer immunology and immunotherapy, CD4+Foxp3+ regulatory T cells, tumor immune microenvironment
