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.

Keywords: CD4+Foxp3+ regulatory T cells; TNF; TNFR2; cancer immunology and immunotherapy; tumor immune microenvironment.

Figure 1

TNFR2, PD-L1, and CTLA-4 gene expression profiles across diverse human cancer and normal tissues. The transcriptomic analyses of indicated gene expression by human cancers and paired normal tissues were performed with GEPIA (Gene Expression Profiling Interactive Analysis) online database (http://gepia2.cancer-pku.cn/); Figure 1 is drawn according to specific data in the GEPIA database. Log-scale was set to log 2 (TPM+1) in the analysis.

Figure 2

Comparison of TNFR2, PD-L1, CTLA-4 gene expression levels by human cancers and paired normal tissues.  The transcriptomic analyses of indicated gene expression by human cancers and paired normal tissues were performed with GEPIA (Gene Expression Profiling Interactive Analysis) online database (http://gepia2.cancer-pku.cn/); Figure 2 is drawn according to specific data in the GEPIA database. Log-scale was set to log 2 (TPM+1) in the analysis. The transcriptomic analyses were performed as described in Y-axis: transcript per million. X-axis: tumor (T, red) and paired normal tissues (N, grey). The number (num) of samples is indicated. The solid black line represents medium value. The box is the upper and lower quartiles and the two lines outside the box stand for the highest and lowest expression levels. Comparison between tumor and paired normal tissue: *p<0.01 (analyzed by one-way ANOVA). Abbreviations: DLBC, lymphoid neoplasm diffuse large B-cell lymphoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KIRC, kidney renal clear cell carcinoma; LGG, brain lower grade glioma; N, normal; PAAD, pancreatic adenocarcinoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TGCT, testicular germ cell tumors; THYM, thymoma; T, tumor.

Figure 3

Current understanding of the role of TNF-TNFR2 signaling in the tumor microenvironment. In the tumor microenvironment (TME), tumor-associated macrophages, effector cells (CD4⁺ and CD8⁺ T effector (Teff) cells and natural killer (NK) cells), and tumor cells are the major source of TNF. In response to TNF stimulation, the number of CD4⁺Foxp3⁺TNFR2⁺ Treg cells are increased. These expanded Treg cells in TME are more stable in phenotype and more immunosuppressive. Moreover, TNF activates TNFR2⁺ myeloid-derived suppressor cells (MDSCs) and TNFR2⁺ mesenchymal stem cells (MSCs). Tregs, MDSCs, and MSCs likely operate collaboratively in the inhibition of the anti-tumor immune response and the promotion of tumor evasion. Further, TNFR2 signaling also promotes the survival, metastasis, and growth of the tumor.