TNFSF9

Last updated

TNFSF9
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TNFSF9 , 4-1BB-L, CD137L, TNLG5A, tumor necrosis factor superfamily member 9, TNF superfamily member 9
External IDs OMIM: 606182; MGI: 1101058; HomoloGene: 55782; GeneCards: TNFSF9; OMA:TNFSF9 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

8744

21950

Ensembl

ENSG00000125657

ENSMUSG00000035678

UniProt

P41273

P41274

RefSeq (mRNA)

NM_003811

NM_009404

RefSeq (protein)

NP_003802

NP_033430

Location (UCSC) Chr 19: 6.53 – 6.54 Mb Chr 17: 57.41 – 57.41 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tumor necrosis factor ligand superfamily member 9 also known as 4-1BB ligand or 4-1BBL or CD137L is a protein that in humans is encoded by the TNFSF9 gene. [5]

Contents

4-1BBL is a type 2 transmembrane glycoprotein receptor that is found on APCs (antigen presenting cells) and binds to 4-1BB (also known as CD137). The 4-1BB/4-1BBL complex belongs to the TNFR:TNF superfamily, [6] which is expressed on activated T Lymphocytes. [7]

Structure of 4-1BB/4-1BBL complex

The 4-1BB/4-1BBL complex consists of three monomeric 4-1BBs bound to a trimeric 4-1BBL. Each 4-1BB monomer binds to two 4-1BBLs via cysteine-rich domains (CRDs). The interaction between 4-1BB and the second 4-1BBL is required to stabilize their interactions. [8] The link with 4-1BBL is largely made up of amino acids from the dynamic loops of the CRD2 and the β sheet of CRD3 of 4-1BB, according to a detailed study of the binding between the 4-1BB and 4-1BBL interface. CRD2 amino acids (T61, Q67, and K69) interact with the AA′ loop (Y110 and G114) and the intra-H-strand loop (Q227 and Q230) of 4-1BBL to form various hydrogen bond interactions. [9]

Application to cancer immunotherapy

Studies on the poorly immunogenic Ag104A sarcoma and the extremely tumorigenic P815 mastocytoma provided the first systematic proof that anti-4-1BB antibodies have potent anti-tumor effects. Anti-4-1BB administration to mice with the aforementioned tumors was shown to substantially inhibit tumor growth by increasing CTL activity. In the years to come, more studies verified and legitimized the effect of 4-1BB signaling to inhibit tumor growth. [10]

The interaction between 4-1BB and 4-1BBL provide costimulatory signals to a variety of T cells, which can be used to discover cancer immunotherapy. The 4-1BB/4-1BBL complex together with a signal provided by a T-cell receptor can provide costimulatory signals to CD4+ and CD8+ T cells in mice, leading to the activation of CD4+ and CD8+ T cells. The activation of CD8+ T cells is essential in antitumor immunity. [6] The 4-1BB/4-1BBL complex with the help of T-cell receptor signals can co-stimulate human CD28− T cells and trigger the increase in CD28− T cells. Unlike the activation of CD8+ T cells, the proliferation of CD28− T cells can negatively affect cancer state and other diseases. Therefore, this pathway can be targeted for immunotherapy. [11]

See also

Related Research Articles

In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specific antigen. The receptors are chimeric in that they combine both antigen-binding and T cell activating functions into a single receptor.

B7 is a type of integral membrane protein found on activated antigen-presenting cells (APC) that, when paired with either a CD28 or CD152 (CTLA-4) surface protein on a T cell, can produce a costimulatory signal or a coinhibitory signal to enhance or decrease the activity of a MHC-TCR signal between the APC and the T cell, respectively. Binding of the B7 of APC to CTLA-4 of T-cells causes inhibition of the activity of T-cells.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.

<span class="mw-page-title-main">CD278</span> Protein found in humans

Inducible T-cell costimulator is an immune checkpoint protein that in humans is encoded by the ICOS gene. The protein belongs to the CD28 and CTLA-4 cell-surface receptor family. These are proteins expressed on the surface of immune cells that mediate signalling between them. A surface protein, the ligand, binds specifically to its receptor on another cell, leading to a signalling cascade in that cell.

<span class="mw-page-title-main">CD80</span> Mammalian protein found in humans

The Cluster of differentiation 80 is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related to CD86, another B7 protein (B7-2), and often works in tandem. Both CD80 and CD86 interact with costimulatory receptors CD28, CTLA-4 (CD152) and the p75 neurotrophin receptor.

<span class="mw-page-title-main">CD86</span> Mammalian protein found in humans

Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.

<span class="mw-page-title-main">CD134</span> Protein-coding gene in humans

Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 and OX40 receptor, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28. OX40 is a secondary co-stimulatory immune checkpoint molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of OX40 is dependent on full activation of the T cell; without CD28, expression of OX40 is delayed and of fourfold lower levels.

OX40L is the ligand for OX40 and is stably expressed on many antigen-presenting cells such as DC2s, macrophages, and activated B lymphocytes.

CD70 is a protein that in humans is encoded by CD70 gene. CD70 is also known as a ligand for CD27.

<span class="mw-page-title-main">CD137</span> Protein found in humans

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. 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.

<span class="mw-page-title-main">CD27</span> Protein in the tumor necrosis factor receptor superfamily

CD27 is a member of the tumor necrosis factor receptor superfamily. It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule, and is the target of an anti-cancer drug in clinical trials.

<span class="mw-page-title-main">PD-L1</span> Mammalian protein found in humans

Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.

<span class="mw-page-title-main">Programmed cell death protein 1</span> Mammalian protein found in humans

Programmed cell death protein 1(PD-1),. PD-1 is a protein encoded in humans by the PDCD1 gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

<span class="mw-page-title-main">ICOSLG</span> Protein-coding gene in the species Homo sapiens

ICOS ligand is a protein that in humans is encoded by the ICOSLG gene located at chromosome 21. ICOSLG has also been designated as CD275.

<span class="mw-page-title-main">HAVCR2</span> Protein-coding gene in the species Homo sapiens

Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3) gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.

<span class="mw-page-title-main">TNFRSF18</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.

Urelumab is a fully human, non‐ligand binding, CD137 agonist immunoglobulin‐γ 4 (IgG4) monoclonal antibody. It was developed utilizing Medarex's UltiMAb(R) technology by Bristol-Myers Squibb for the treatment of cancer and solid tumors. Urelumab promotes anti-tumor immunity, or an immune response against tumor cells, via CD137 activation. The application of Urelumab has been limited because it can cause severe liver toxicity.

<span class="mw-page-title-main">Immune checkpoint</span> Regulators of the immune system

Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.

<span class="mw-page-title-main">CD28 family receptor</span> Group of regulatory cell surface receptors

CD28 family receptors are a group of regulatory cell surface receptors expressed on immune cells. The CD28 family in turn is a subgroup of the immunoglobulin superfamily.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000125657 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000035678 – 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. 56 (1): 32–39. doi:10.1038/s12276-023-01136-4. PMC   10834507 . PMID   38172595.
  6. 1 2 Cheuk AT, Mufti GJ, Guinn BA (March 2004). "Role of 4-1BB:4-1BB ligand in cancer immunotherapy". Cancer Gene Therapy. 11 (3): 215–26. doi:10.1038/sj.cgt.7700670. PMID   14671675. S2CID   11429744.
  7. ↑ Lotze M (2001). Dendritic Cells. Boston: Academic Press. ISBN   0-12-455851-8.
  8. ↑ Li Y, Tan S, Zhang C, Chai Y, He M, Zhang CW, et al. (October 2018). "Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab". Cell Reports. 25 (4): 909–920.e4. doi: 10.1016/j.celrep.2018.09.073 . PMID   30355497.
  9. ↑ Li Y, Tan S, Zhang C, Chai Y, He M, Zhang CW, Wang Q, Tong Z, Liu K, Lei Y, Liu WJ (October 2018). "Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab". Cell Reports. 25 (4): 909–920.e4. doi: 10.1016/j.celrep.2018.09.073 . ISSN   2211-1247. PMID   30355497.
  10. ↑ Vinay DS, Kwon BS (2012-05-01). "Immunotherapy of Cancer with 4-1BB". Molecular Cancer Therapeutics. 11 (5): 1062–1070. doi: 10.1158/1535-7163.MCT-11-0677 . ISSN   1535-7163. PMID   22532596.
  11. ↑ Bukczynski J, Wen T, Watts TH (February 2003). "Costimulation of human CD28- T cells by 4-1BB ligand". European Journal of Immunology. 33 (2): 446–54. doi:10.1002/immu.200310020. PMID   12645943. S2CID   38395011.


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