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:

• TNF
• TNFR2
• cancer immunology and immunotherapy
• CD4⁺Foxp3⁺ regulatory T cells
• tumor immune microenvironment

Abbreviations

CTLA-4, Cytotoxic T Lymphocyte Antigen-4; PD-1, Programmed Death-1; PD-L1, Programmed Death-Ligand 1; TNF,Tumor Necrosis Factor; TNFR1, Tumor Necrosis Factor Receptor Type I; TNFR2, Tumor Necrosis Factor Receptor Type II; Foxp3, Forkhead Box P3; Tregs, Regulatory T cells; Teffs, Effector T cells; MDSCs, Myeloid-Derived Suppressor Cells; MSCs, Mesenchymal Stem Cells; ECs, Endothelial Cells; EPCs, Endothelial Progenitor Cells; NK cells, Natural Killer Cells; Bregs, Regulatory B cells; CTL, Cytotoxic T Cells; TIL, Tumor-Infiltrating Lymphocytes; ICIs, Immune Checkpoint Inhibitors; FDA, The United States Food and Drug Administration; irAEs, Immune-Related Adverse Events; TIM3,T cell Immunoglobulin and Mucin Domain-containing Protein 3; LAG3, Lymphocyte-Activation Gene 3; TIGIT, T cell Immunoglobulin (Ig) and Immunoreceptor Tyrosine-based Inhibition Motif (ITIM) domain; IL-10, Interleukin-10; IL-35, Interleukin-35; TGFβ, Transforming Growth Factor-beta; NF-κB, Nuclear Factor Kappa B; sTNF, Soluble TNF; mTNF, Transmembrane TNF; DCs, Dendritic Cells; WT, Wild-Type; KO, Knock-Out; IKKα, IκB Kinase alpha; Akt, Protein Kinase B; Smad3, Mothers Against Decapentaplegic Homolog 3; Th1, T Helper Type 1; Th17, T Helper Type 17; mTOR, Mammalian Target of Rapamycin; PI3K, Phosphatidylinositol 3-Kinase; Erk1/2, Extracellular Signal-Regulated Protein Kinase 1/2; MAPK, Mitogen-Activated Protein Kinase; JNK, Jun N-Terminal Kinases; Tconvs, Conventional T cells; tTregs, Thymus-derived Treg cells; TCA, Tricarboxylic Acid Cycle; nTregs, Naturally-occurring Treg cells; iTregs, Induced Treg cells; EAE, Experimental Autoimmune Encephalomyelitis; TME, Tumor Microenvironment; LLC, Lewis Lung Carcinoma; TCGA, The Cancer Genome Atlas; GTEx, Genotype-Tissue Expression; GEPIA, Gene Expression Profiling Interactive Analysis; SS, Sézary Syndrome; IHC, Immunohistochemistry; NSCLC, Non-Small Cell Lung Carcinoma; ESCC, Esophageal Squamous Cell Carcinoma; DLBC, Lymphoid Neoplasm Diffuse Large B-Cell Lymphoma; THYM, Thymoma; M/R, Methionine or Arginine; PARP, Poly (ADP-ribose) Polymerase; sTNFR2, Soluble TNFR2; CXCR4, C-X-C Chemokine Receptor Type 4; VEGF, Vascular Endothelial Growth Factor; IL-8, Interleukin-8; mAbs, Monoclonal Antibodies; AICD, Activation-Induced Cell Death; IFNγ, Interferon Gamma; IL-2, Interleukin-2; RA, Rheumatoid Arthritis; IMiDs, Immunomodulatory Drugs; IL-6, Interleukin-6; IL-12, Interleukin-12; CLL, Chronic Lymphocytic Leukemia; CpG ODN, CpG Oligodeoxynucleotide; T1D, Type 1 Diabetes; GvHD, Graft Versus Host Disease; ADCC, Antibody-Dependent Cellular Cytotoxicity; IL-15, Interleukin-15; IL-15Rα, Interleukin-15 Receptor alpha; T, Tumor; N, Normal; ACC, Adrenocortical Carcinoma; BLCA, Bladder Urothelial Carcinoma; CESC, Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma; CHOL, Cholangiocarcinoma; COAD, Colon Adenocarcinoma; ESCA, Esophageal Carcinoma; GBM, Glioblastoma Multiforme; HNSC, Head and Neck Squamous Cell Carcinoma; KICH, Kidney Chromophobe; KIRC, Kidney Renal Clear Cell Carcinoma; KIRP, Kidney Renal Papillary Cell Carcinoma; LAML, Acute Myeloid Leukemia; LGG, Brain Lower Grade Glioma; LIHC, Hepatocellular Carcinoma; OV, Ovarian Serous Cystadenocarcinoma; PAAD, Pancreatic Adenocarcinoma; PCPG, Pheochromocytoma and Paraganglioma; PRAD, Prostate Adenocarcinoma; READ, Rectum Adenocarcinoma; SARC, Sarcoma; SKCM, Skin Cutaneous Melanoma; STAD, Stomach Adenocarcinoma; TGCT, Testicular Germ Cell Tumors; THCA, Thyroid Carcinoma; UCEC, Uterine Corpus Endometrial Carcinoma; UCS, Uterine Carcinosarcoma; RCC, Renal Cell Carcinoma; SCLC, Small Cell Lung Cancer; IgG, Immunoglobulin G; Sca1, Stem Cell Antigen-1; DMBA, 7, 12-dimethylbenzanthracene; TPA, 12-O-tetradecanoylphorbol-13-acetate.

Acknowledgements

This project was funded by The Science and Technology Development Fund, Macau SAR (FDCT, File No. 201/2017/A3 and 0056/2019/AFJ) and University of Macau (File No. MYRG2016-00023-ICMS-QRCM, MYRG2017-00120-ICMS, MYRG2019-00169-ICMS and CPG202-00007-ICMS).

Disclosure

The authors report no conflicts of interest in this work.