CD137

CD137, a member of the tumor necrosis factor (TNF) receptor family, is a type 1 transmembrane protein, expressed on surfaces of leukocytes and non-immune cells.^[5][6] Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB, and induced by lymphocyte activation (ILA). It is of interest to immunologists as a co-stimulatory immune checkpoint molecule, and as a potential target in cancer immunotherapy.

TNFRSF9
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1D0J
Identifiers
Aliases	TNFRSF9, 4-1BB, CD137, CDw137, ILA, tumor necrosis factor receptor superfamily member 9, TNF receptor superfamily member 9
External IDs	OMIM: 602250; MGI: 1101059; HomoloGene: 1199; GeneCards: TNFRSF9; OMA:TNFRSF9 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)^[1] Band 1p36.23 Start 7,915,871 bp^[1] End 7,943,165 bp^[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)^[2] Band 4 E2|4 81.52 cM Start 150,999,019 bp^[2] End 151,030,559 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in lymph node blood appendix monocyte gallbladder thymus thymus pancreatic ductal cell spleen rectum Top expressed in thymus lymph node islet of Langerhans uterus morula blood spleen subcutaneous adipose tissue body of femur Region I of hippocampus proper More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytokine binding tumor necrosis factor-activated receptor activity signaling receptor activity Cellular component integral component of membrane integral component of plasma membrane membrane external side of plasma membrane extracellular space plasma membrane Biological process multicellular organism development regulation of apoptotic process response to lipopolysaccharide inflammatory response immune response protein homotrimerization apoptotic process negative regulation of cell population proliferation tumor necrosis factor-mediated signaling pathway regulation of cell population proliferation apoptotic signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3604 21942 Ensembl ENSG00000049249 ENSMUSG00000028965 UniProt Q07011 P20334 RefSeq (mRNA) NM_001561 NM_001077508 NM_001077509 NM_011612 RefSeq (protein) NP_001552 NP_001070976 NP_001070977 NP_035742 Location (UCSC) Chr 1: 7.92 – 7.94 Mb Chr 4: 151 – 151.03 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Expression

CD137 is only expressed on the cell surface after T cell activation. When T cells are activated by Antigen Presenting Cells (APCs), CD137 becomes embedded in CD4+ and CD8+ T cells.^[5]

CD137 is a costimulatory molecule functioning to stimulate T cell proliferation, dendritic cell maturation, and promotion of B cell antibody secretion.^[7] As a T cell co-stimulator, T cell receptor (TCR) and CD28 signaling causes expression of CD137 on T cell membranes. When CD137 then reacts with the CD137 ligand, it leads to CD137 upregulation.^[7] This is a form of self regulation or positive feedback cycle. When CD137 interacts with its ligand, it leads to T cell cytokine production and T cell proliferation, among other signaling pathway responses.

Other cells that express CD137 include both immune cells (i.e. monocytes, natural killer cells, dendritic cells, follicular dendritic cells (FDCs), and regulatory T cells) and non-immune cells (i.e. chondrocytes, neurons, astrocytes, microglia and endothelial cells).^[7]

Regulation of the immune system

CD137 and its ligand both induce signaling cascades upon interaction, a phenomenon known as bidirectional signal transduction. The CD137/ligand complex is also involved in regulation of the immune system. The CD137 ligand is a type-II transmembrane glycoprotein expressed on APCs.^[8] The CD137 ligand is normally expressed at low levels, but can have increased expression in presence of pathogen associated molecular patterns (PAMPs) or proinflammatory immune responses like IL-1 secretion.

Cross-linking CD137 and active T cells can not only result in T cell proliferation via increased IL-2 secretion, but surviving cells also contribute to expanding immune system memory and augmenting T cell cytolytic activity.^[8]

Atherosclerosis

Inflammation

Atherosclerosis is a disease, linked to Cardiovascular Disease (CVD), and associated with cardiac inflammation, in the form of lesions in the walls of the atrial chambers and other vasculature.^[9] Treatments designed to target the CD137 molecules expressed on immune cell surfaces often lead to T cell proliferation as CD137 stimulation allows for the T cells to continue through the cell cycle. In this way, CD137 is often referred to as an immune checkpoint. This proliferation eventually leads to other immune cell responses and secretion of proinflammatory cytokines which result in exaggerated inflammatory responses that exacerbate atherosclerosis.^[9] Ongoing studies are researching CD137 as a biomarker for atherosclerosis as well as CD137 antagonists as potential therapeutics to reduce the symptoms associated with the condition.

Endothelial cells

The mechanism connecting CD137 bidirectional signaling to the promotion of atherosclerosis is related to CD137 mediation of epithelial cell damage. When the CD137/CD137L complex interacts with endothelial cells, including those lining vascular structures, it induces the upregulation of molecules that promote inflammation and damage. For instance, increases in adhesion molecules, including vascular adhesion molecule-1 or intracellular adhesion molecule-1, on epithelial cells causes recruitment of immune cells like macrophages and neutrophils.^[10] When they arrive, these cells initiate proinflammatory responses including cytokine secretion. In chronic cases, this results in excessive inflammation of the epithelial tissue, leading to cell damage and the formation of atherosclerotic inflammatory lesions.^[10]

Interactions

CD137 has been shown to interact with TRAF2.^[11][12]

As a drug target

Cancer immunotherapy

CD137 is also involved in cancer having been found upregulated in cancerous cell lines. CD137/ligand stimulation has been found to lead to stronger anti-tumor responses due to cytotoxic T cell activation and is being examined as a possible anticancer therapy.^[13]

Current cancer immunotherapy treatments use monoclonal antibodies (mAbs) to target and kill cancer cells. Cancer cells upregulate cell surface CD137, however the reason behind this remains unclear. What is known is the fact that mAbs targeting CD137 are successful in fighting cancer as they can not only mark cancer cells, but they allow for CD8+ T cell activation and increased IFN-gamma secretion as per CD137’s function as a costimulatory molecule.^[14] This enables the affected individual’s immune system to actively target and kill cancer cells that express CD137 on their cell surfaces. Currently, Utomilumab is the only mAb targeting CD137 on the market.^[15] Urelumab trials were temporarily halted due to risk of liver toxicity. Utomilumab trials resulted in the drug’s being cleared for therapeutic use.

Utomilumab

Utomilumab (PF-05082566) targets this receptor to stimulate a more intense immune system attack on cancers.^[16] It is a fully human IgG2 monoclonal antibody.^[17] It is in early clinical trials.^[16] As of June 2016^[update], 5 clinical trials are active.^[18] In recent years, there has been a reignited interest in 4-1BB immunotherapy. Currently, there are several anti-4-1BB antibodies and recombinant proteins are in various stages of clinical trial.^[5]

See also

• 4-1BB ligand
• Urelumab

References

1. GRCh38: Ensembl release 89: ENSG00000049249 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000028965 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Singh R, Kim YH, Lee SJ, Eom HS, Choi BK (Feb 2024). "4-1BB immunotherapy: advances and hurdles". Experimental & Molecular Medicine volume. 56 (1): 32–39. doi:10.1038/s12276-023-01136-4. PMC 10834507. PMID 38172595.
6. Thum E, Shao Z, Schwarz H (January 2009). "CD137, implications in immunity and potential for therapy". Frontiers in Bioscience. 14 (11): 4173–4188. doi:10.2741/3521. PMID 19273343.
7. Thum E, Shao Z, Schwarz H (January 2009). "CD137, implications in immunity and potential for therapy". Frontiers in Bioscience. 14 (11): 4173–4188. doi:10.2741/3521. PMID 19273343.
8. Thum E, Shao Z, Schwarz H (January 2009). "CD137, implications in immunity and potential for therapy". Frontiers in Bioscience. 14 (11): 4173–4188. doi:10.2741/3521. PMID 19273343.
9. Söderström LÅ, Tarnawski L, Olofsson PS (May 2018). "CD137: A checkpoint regulator involved in atherosclerosis". Atherosclerosis. 272: 66–72. doi:10.1016/j.atherosclerosis.2018.03.007. PMID 29571029.
10. Yuan W, Xu C, Li B, Xia H, Pan Y, Zhong W, et al. (June 2021). "Contributions of Costimulatory Molecule CD137 in Endothelial Cells". Journal of the American Heart Association. 10 (11): e020721. doi:10.1161/JAHA.120.020721. PMC 8483511. PMID 34027676.
11. Jang IK, Lee ZH, Kim YJ, Kim SH, Kwon BS (January 1998). "Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B". Biochemical and Biophysical Research Communications. 242 (3): 613–620. doi:10.1006/bbrc.1997.8016. PMID 9464265.
12. Arch RH, Thompson CB (January 1998). "4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB". Molecular and Cellular Biology. 18 (1): 558–565. doi:10.1128/MCB.18.1.558. PMC 121523. PMID 9418902.
13. Makkouk A, Chester C, Kohrt HE (February 2016). "Rationale for anti-CD137 cancer immunotherapy". European Journal of Cancer. 54: 112–119. doi:10.1016/j.ejca.2015.09.026. PMID 26751393.
14. Chu DT, Bac ND, Nguyen KH, Tien NL, Thanh VV, Nga VT, et al. (April 2019). "An Update on Anti-CD137 Antibodies in Immunotherapies for Cancer". International Journal of Molecular Sciences. 20 (8): 1822. doi:10.3390/ijms20081822. PMC 6515339. PMID 31013788.
15. Jhajj HS, Lwo TS, Yao EL, Tessier PM (January 2023). "Unlocking the potential of agonist antibodies for treating cancer using antibody engineering". Trends in Molecular Medicine. 29 (1): 48–60. doi:10.1016/j.molmed.2022.09.012. PMC 9742327. PMID 36344331.
16. "Pfizer cancer drug shows promise in combo with Merck's Keytruda". Reuters. May 2016.
17. Thall A (May 2016). Phase 1 Study of Utomilumab (PF-05082566) In Combination with Rituximab in Patients with CD20+ NHL (PDF). New Therapies in Hematology. Bologna, Italy. Study B1641001).
18. "PF-05082566 clinical trials". clinicaltrials.gov.

External links

• Human TNFRSF9 genome location and TNFRSF9 gene details page in the UCSC Genome Browser.

Further reading

• Kwon BS, Weissman SM (March 1989). "cDNA sequences of two inducible T-cell genes". Proceedings of the National Academy of Sciences of the United States of America. 86 (6): 1963–1967. Bibcode:1989PNAS...86.1963K. doi:10.1073/pnas.86.6.1963. PMC 286825. PMID 2784565.
• Schwarz H, Tuckwell J, Lotz M (December 1993). "A receptor induced by lymphocyte activation (ILA): a new member of the human nerve-growth-factor/tumor-necrosis-factor receptor family". Gene. 134 (2): 295–298. doi:10.1016/0378-1119(93)90110-O. PMID 8262389.
• Sica G, Chen L (2000). "Biochemical and immunological characteristics of 4-1BB (CD137) receptor and ligand and potential applications in cancer therapy". Archivum Immunologiae et Therapiae Experimentalis. 47 (5): 275–279. PMID 10604232.
• Schwarz H (March 2005). "Biological activities of reverse signal transduction through CD137 ligand". Journal of Leukocyte Biology. 77 (3): 281–286. doi:10.1189/jlb.0904558. PMID 15618293.
• Kwon BS, Weissman SM (March 1989). "cDNA sequences of two inducible T-cell genes". Proceedings of the National Academy of Sciences of the United States of America. 86 (6): 1963–1967. Bibcode:1989PNAS...86.1963K. doi:10.1073/pnas.86.6.1963. PMC 286825. PMID 2784565.
• Zhou Z, Kim S, Hurtado J, Lee ZH, Kim KK, Pollok KE, Kwon BS (February 1995). "Characterization of human homologue of 4-1BB and its ligand". Immunology Letters. 45 (1–2): 67–73. doi:10.1016/0165-2478(94)00227-I. PMID 7622190.
• Alderson MR, Smith CA, Tough TW, Davis-Smith T, Armitage RJ, Falk B, et al. (September 1994). "Molecular and biological characterization of human 4-1BB and its ligand". European Journal of Immunology. 24 (9): 2219–2227. doi:10.1002/eji.1830240943. PMID 8088337. S2CID 35822854.
• Schwarz H, Tuckwell J, Lotz M (December 1993). "A receptor induced by lymphocyte activation (ILA): a new member of the human nerve-growth-factor/tumor-necrosis-factor receptor family". Gene. 134 (2): 295–298. doi:10.1016/0378-1119(93)90110-O. PMID 8262389.
• Schwarz H, Blanco FJ, von Kempis J, Valbracht J, Lotz M (April 1996). "ILA, a member of the human nerve growth factor/tumor necrosis factor receptor family, regulates T-lymphocyte proliferation and survival". Blood. 87 (7): 2839–2845. doi:10.1182/blood.V87.7.2839.bloodjournal8772839. PMID 8639902.
• Loo DT, Chalupny NJ, Bajorath J, Shuford WW, Mittler RS, Aruffo A (March 1997). "Analysis of 4-1BBL and laminin binding to murine 4-1BB, a member of the tumor necrosis factor receptor superfamily, and comparison with human 4-1BB". The Journal of Biological Chemistry. 272 (10): 6448–6456. doi:10.1074/jbc.272.10.6448. PMID 9045669.
• Schwarz H, Arden K, Lotz M (June 1997). "CD137, a member of the tumor necrosis factor receptor family, is located on chromosome 1p36, in a cluster of related genes, and colocalizes with several malignancies". Biochemical and Biophysical Research Communications. 235 (3): 699–703. doi:10.1006/bbrc.1997.6870. PMID 9207223.
• Arch RH, Thompson CB (January 1998). "4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB". Molecular and Cellular Biology. 18 (1): 558–565. doi:10.1128/MCB.18.1.558. PMC 121523. PMID 9418902.
• Jang IK, Lee ZH, Kim YJ, Kim SH, Kwon BS (January 1998). "Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B". Biochemical and Biophysical Research Communications. 242 (3): 613–620. doi:10.1006/bbrc.1997.8016. PMID 9464265.
• Kim YJ, Kim SH, Mantel P, Kwon BS (March 1998). "Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses". European Journal of Immunology. 28 (3): 881–890. doi:10.1002/(SICI)1521-4141(199803)28:03<881::AID-IMMU881>3.0.CO;2-0. PMID 9541583.
• Saoulli K, Lee SY, Cannons JL, Yeh WC, Santana A, Goldstein MD, et al. (June 1998). "CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand". The Journal of Experimental Medicine. 187 (11): 1849–1862. doi:10.1084/jem.187.11.1849. PMC 2212301. PMID 9607925.
• Langstein J, Michel J, Schwarz H (November 1999). "CD137 induces proliferation and endomitosis in monocytes". Blood. 94 (9): 3161–3168. doi:10.1182/blood.V94.9.3161. PMID 10556203.
• Jang LK, Lee ZH, Kim HH, Hill JM, Kim JD, Kwon BS (December 2001). "A novel leucine-rich repeat protein (LRR-1): potential involvement in 4-1BB-mediated signal transduction". Molecules and Cells. 12 (3): 304–312. doi:10.1016/S1016-8478(23)25210-3. PMID 11804328.
• Cooper D, Bansal-Pakala P, Croft M (February 2002). "4-1BB (CD137) controls the clonal expansion and survival of CD8 T cells in vivo but does not contribute to the development of cytotoxicity". European Journal of Immunology. 32 (2): 521–529. doi:10.1002/1521-4141(200202)32:2<521::AID-IMMU521>3.0.CO;2-X. PMID 11828369.
• Wilcox RA, Chapoval AI, Gorski KS, Otsuji M, Shin T, Flies DB, et al. (May 2002). "Cutting edge: Expression of functional CD137 receptor by dendritic cells". Journal of Immunology. 168 (9): 4262–4267. doi:10.4049/jimmunol.168.9.4262. PMID 11970964.
• Shulzhenko N, Morgun A, Chinellato AP, Rampim GF, Diniz RV, Almeida DR, Gerbase-DeLima M (March 2002). "CD27 but not CD70 and 4-1BB intragraft gene expression is a risk factor for acute cardiac allograft rejection in humans". Transplantation Proceedings. 34 (2): 474–475. doi:10.1016/S0041-1345(02)02600-3. PMID 12009595.
• Pauly S, Broll K, Wittmann M, Giegerich G, Schwarz H (July 2002). "CD137 is expressed by follicular dendritic cells and costimulates B lymphocyte activation in germinal centers". Journal of Leukocyte Biology. 72 (1): 35–42. doi:10.1189/jlb.72.1.35. PMID 12101260. S2CID 17908504.
• Singh R, Kim YH, Lee SJ, Eom HS, Choi BK (Feb 2024). "4-1BB immunotherapy: advances and hurdles". Experimental & Molecular Medicine volume. 56 (1): 32–39. doi:10.1038/s12276-023-01136-4. PMC 10834507. PMID 38172595. S2CID 266744295.