CD137 explained

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.[1] [2] 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.

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.[3]

CD137 is a costimulatory molecule functioning to stimulate T cell proliferation, dendritic cell maturation, and promotion of B cell antibody secretion.[4] 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. 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).

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.[5] 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.

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.[6] 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. 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.[7] 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.

Interactions

CD137 has been shown to interact with TRAF2.[8] [9]

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.[10]

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.[11] 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.[12] 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.[13] It is a fully human IgG2 monoclonal antibody.[14] It is in early clinical trials.[13], 5 clinical trials are active.[15] 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.[16]

See also

Further reading

Notes and References

  1. Singh R, Kim YH, Lee SJ, Eom HS, Choi BK . 4-1BB immunotherapy: advances and hurdles . Experimental & Molecular Medicine volume . 56 . 1 . 32–39 . Feb 2024 . 38172595 . 10.1038/s12276-023-01136-4 . 10834507 .
  2. Thum E, Shao Z, Schwarz H . CD137, implications in immunity and potential for therapy . Frontiers in Bioscience . 14 . 11 . 4173–4188 . January 2009 . 19273343 . 10.2741/3521 . free .
  3. Singh R, Kim YH, Lee SJ, Eom HS, Choi BK . 4-1BB immunotherapy: advances and hurdles . Experimental & Molecular Medicine volume . 56 . 1 . 32–39 . Feb 2024 . 38172595 . 10.1038/s12276-023-01136-4 . 10834507 .
  4. Thum E, Shao Z, Schwarz H . CD137, implications in immunity and potential for therapy . Frontiers in Bioscience . 14 . 11 . 4173–4188 . January 2009 . 19273343 . 10.2741/3521 . free .
  5. Thum E, Shao Z, Schwarz H . CD137, implications in immunity and potential for therapy . Frontiers in Bioscience . 14 . 11 . 4173–4188 . January 2009 . 19273343 . 10.2741/3521 . free .
  6. Söderström LÅ, Tarnawski L, Olofsson PS . CD137: A checkpoint regulator involved in atherosclerosis . English . Atherosclerosis . 272 . 66–72 . May 2018 . 29571029 . 10.1016/j.atherosclerosis.2018.03.007 .
  7. Yuan W, Xu C, Li B, Xia H, Pan Y, Zhong W, Xu L, Chen R, Wang B . 6 . Contributions of Costimulatory Molecule CD137 in Endothelial Cells . Journal of the American Heart Association . 10 . 11 . e020721 . June 2021 . 34027676 . 8483511 . 10.1161/JAHA.120.020721 .
  8. Jang IK, Lee ZH, Kim YJ, Kim SH, Kwon BS . Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B . Biochemical and Biophysical Research Communications . 242 . 3 . 613–620 . January 1998 . 9464265 . 10.1006/bbrc.1997.8016 .
  9. Arch RH, Thompson CB . 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 . January 1998 . 9418902 . 121523 . 10.1128/MCB.18.1.558 .
  10. Makkouk A, Chester C, Kohrt HE . Rationale for anti-CD137 cancer immunotherapy . European Journal of Cancer . 54 . 112–119 . February 2016 . 26751393 . 10.1016/j.ejca.2015.09.026 .
  11. Chu DT, Bac ND, Nguyen KH, Tien NL, Thanh VV, Nga VT, Ngoc VT, Anh Dao DT, Hoan LN, Hung NP, Trung Thu NT, Pham VH, Vu LN, Pham TA, Thimiri Govinda Raj DB . 6 . An Update on Anti-CD137 Antibodies in Immunotherapies for Cancer . International Journal of Molecular Sciences . 20 . 8 . 1822 . April 2019 . 31013788 . 6515339 . 10.3390/ijms20081822 . free .
  12. Jhajj HS, Lwo TS, Yao EL, Tessier PM . Unlocking the potential of agonist antibodies for treating cancer using antibody engineering . English . Trends in Molecular Medicine . 29 . 1 . 48–60 . January 2023 . 36344331 . 9742327 . 10.1016/j.molmed.2022.09.012 .
  13. Web site: Pfizer cancer drug shows promise in combo with Merck's Keytruda . May 2016 . Reuters .
  14. Thall A . New Therapies in Hematology . Bologna, Italy . May 2016 . Phase 1 Study of Utomilumab (PF-05082566) In Combination with Rituximab in Patients with CD20+ NHL . Study B1641001) .
  15. Web site: PF-05082566 clinical trials . clinicaltrials.gov .
  16. Singh R, Kim YH, Lee SJ, Eom HS, Choi BK . 4-1BB immunotherapy: advances and hurdles . Experimental & Molecular Medicine volume . 56 . 1 . 32–39 . Feb 2024 . 38172595 . 10.1038/s12276-023-01136-4 . 10834507 .

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