TNFR2: Role in Cancer Immunology and Immunotherapy

Figures & data

Table 1 FDA-Approved Immune Checkpoint Inhibitors (ICIs) for Cancer Treatment

Drug (Trade Name and Company Name)	Target	Approval Date	Approved Indication	Immune-Related Adverse Events (irAEs)	Reference
Ipilimumab (Yervoy^®, Bristol-Myers Squibb Co.)	CTLA-4	28 March 2011	Advanced metastatic melanoma Renal cell carcinoma (RCC) Colorectal cancer Non-small cell lung cancer (NSCLC) Hepatocellular carcinoma Malignant Pleural Mesothelioma	Hypophysitis Colitis Dermatitis (rash) Hepatitis Nephritis	^Citation193^–^Citation195
Pembrolizumab (Keytruda^®, Merck & Co.)	PD-1	4 September 2014	Advanced melanoma NSCLC Small cell lung cancer (SCLC) Head and neck squamous cell cancer Classical Hodgkin lymphoma Primary mediastinal large B-Cell lymphoma Urothelial Carcinoma Microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer Gastric cancer Cervical cancer Hepatocellular carcinoma Merkel cell carcinoma RCC Tumor mutational burden-high cancer Cutaneous squamous cell carcinoma Esophageal cancer Endometrial cancer	Pneumonitis Colitis Hepatitis Rash Hypothyroidism Hyperthyroidism Type-1 diabetes (T1D) Hypophysitis Nephritis	^Citation193,Citation194,Citation196
Nivolumab (Opdivo^®; Bristol-Myers Squibb Co.)	PD-1	22 December 2014	Advanced melanoma Advanced SCLC and NSCLC Advanced RCC Classical Hodgkin’s lymphoma Head and neck squamous cell carcinoma Urothelial cancer Colorectal cancer Hepatocellular cancer Malignant pleural mesothelioma Esophageal squamous cell carcinoma	Pneumonitis Colitis Hepatitis Rash Hypothyroidism Hyperthyroidism T1D Hypophysitis Nephritis	^Citation193,Citation196
Atezolizumab (Tecentriq^®, Roche)	PD-L1	18 May 2016	Locally advanced or metastatic urothelial carcinoma NSCLC SCLC Metastatic triple-negative breast cancer Hepatocellular cancer Advanced melanoma	Pneumonitis Colitis Hepatitis Hypothyroidism Hyperthyroidism T1D Hypophysitis	^Citation193,Citation196
Avelumab (Bavencio^®, Merck KGaA & Pfizer)	PD-L1	23 March 2017	Metastatic Merkel cell carcinoma Advanced or metastatic urothelial carcinoma Renal cell carcinoma	Pneumonitis Colitis Hepatitis Hypothyroidism T1D Nephritis	^Citation193,Citation196
Durvalumab (Imfinzi^®, AstraZeneca)	PD-L1	01 May 2017	Locally advanced or metastatic urothelial carcinoma Stage III NSCLC	Pneumonitis Colitis Hepatitis Rash Hypothyroidism Hyperthyroidism T1D Hypophysitis Nephritis	^Citation193,Citation196
Cemiplimab (Libtayo^®, Sanofi/Regeneron)	PD-1	28 September 2018	Metastatic or locally advanced cutaneous squamous cell carcinoma	Rash Pneumonitis Hypothyroidism	^Citation193,Citation197

Table 2 Effect of TNFR2-Targeting Treatment on Experimental Tumor Models

Therapeutics Agents	Types of Tumor Model	Studies Outcomes	Reference
Anti-mouse TNFR2 antagonistic antibody (TY101) (Mouse IgG1)	Mice colorectal cancer (CT26 & MC-38)	Monotherapy, or in combination with anti-PD-1, inhibited tumor growth. ^a Induced death of tumor-infiltrating Tregs, increased IFNγ^+ CD8^+ CTLs. Concurrent or a prior dose of TY101 with anti-PD-1 showed maximum benefits. The prior dose of anti-PD-1 with TY101 should be avoided.	^Citation84
Anti-mouse TNFR2 agonist antibody (Y9) (Mouse IgG1)	Various syngeneic mice tumor model	Expanded and improved tumor antigen-specific IFNγ^+ CD8^+ CTLs. Reduced surface TNFR2 expression on tumor-infiltrating CD8^+ T cells and CD4^+ T cells. No change in Treg population, but soluble TNFR2 increased. Response rate varied (CR: CT26, EMT6, WEHI-164, MC-38, Sa1/N, and MBT-2; Without CR: A20; NR: 4T1, B16-F10, and LLC1).^b Combination with anti-PD-1 or anti-PD-L1 improved survival rate and anti-tumor response (WEHI-164, CT26, and EMT6). The toxicity profile was better than anti-CTLA-4.	^Citation159
Ab1 (chimeric antibody) and Ab2 (Humanized form) (Human IgG1)	Humanized mouse models (HT-29, MDA-MB-231, and LG1306)	Increasesd activity and proliferation of CD8^+ and CD4^+ T cells. Monotherapy, or in combination with anti-PD-1, inhibited tumor growth. Combination treatments were more efficacious than anti-PD-1 alone.
TNFR2 antagonistic antibody	Sézary syndrome (SS)	Killed TNFR2^+ SS tumor cells and TNFR2^+ Treg cells of SS subjects. Expanded the CD8^+ Teff cells. Restored CD26^− subpopulations. Reset Treg/Teff ratio to normal.	^Citation85
TNFR2 blocking antibody (M861) (Mouse IgG)	Mice colorectal cancer (CT26)	Combination with CpG ODN inhibited the tumor growth. Reduced the proportion of TNFR2^+ Treg cells and enhanced the IFNγ^+ CD8^+ CTLs in the tumor-infiltrating lymphocytes.	^Citation88
TNFR2 antagonistic antibody (IgG)	Human ovarian cancer (OVCAR3)	In vitro killing of the tumor. Suppressed the activity of tumor-associated CD4^+ Treg cells. Little inhibitory effects on peripheral CD4^+ Treg cells or cells from healthy donors. Enhanced proliferation of CD8^+ Teff cells.	^Citation99
Anti-mouse TNFR2 agonists (TR75-54.7 and TR75-89) (Hamster IgG)	Mice colorectal cancer (CT26)	Enhanced anti-tumor activity. Improved median survival time.^c Increased IFNγ^+ CD8^+ CTLs. Reset Teff/Treg ratio to normal.	^Citation97
Azacitidine + panobinostat/azacitidine + lenalidomide	Acute myeloid leukemia	Decreased TNFR2^+ Treg cells in the peripheral blood and bone marrow of LAML patients. No change in TNFR2^− Treg cells. Increased in cytokines [IL-2 and IFNγ] production by effector T cells. Panobinostat and lenalidomide repressed the expression of TNFR2 on Treg cells.	^Citation178,Citation198

Notes: ^aCure Rate (complete tumor regression and elimination): In CT26‐tumor implanted animals, TY101 alone: 55%, Anti-PD-1: 25%, and TY101+Anti-PD-1: 62%. In MC38‐tumor implanted animals, TY101 alone: 20%, Anti-PD-1: 10%, and TY101+Anti-PD-1: 70%. ^bComplete Response (CR): Tumor below 60 mm³ and continued to regress until the end of the study. NR: No Response. ^cMedian survival: Control: 22 days; Hamster IgG control mAbs: 25 days; TR75-89: 30.5 days; TR75-54.7: 36 days.

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.¹⁹⁹ Log-scale was set to log 2 (TPM+1) in the analysis.

Abbreviations: 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.

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.¹⁹⁹ 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.

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