TNFRSF9

Official Full Name

TNF receptor superfamily member 9

Organism

Homo sapiens

GeneID

3604

Background

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. The expression of this receptor is induced by lymphocyte activation. TRAF adaptor proteins have been shown to bind to this receptor and transduce the signals leading to activation of NF-kappaB. [provided by RefSeq, Jul 2008]

Synonyms

ILA; 4-1BB; CD137; CDw137; IMD109;

Bio Chemical Class

Cytokine receptor

Protein Sequence

MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL

Open

Disease

Acute myeloid leukaemia, B-cell lymphoma, Immune system disease, Lymphoma, Malignant haematopoietic neoplasm, Mature B-cell lymphoma, Melanoma, Non-small-cell lung cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

20 +

Discontinued Drug

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Detailed Information

The TNFRSF9 gene, also known as 4-1BB or CD137, is located on human chromosome 1p36.22 and comprises 9 exons. It encodes a type I transmembrane protein with a molecular weight of approximately 42–55 kDa. As a member of the tumor necrosis factor receptor superfamily, TNFRSF9 features an extracellular domain with four characteristic cysteine-rich domains (CRDs), forming a rigid scaffold for ligand binding. Although the intracellular region lacks intrinsic enzymatic activity, it contains a conserved TRAF-binding motif, particularly at the C-terminal region, which recruits TRAF1, TRAF2, and TRAF3, and is essential for downstream signaling. Structural studies show that 4-1BB exists as a pre-assembled trimer on the cell membrane, and ligand engagement induces conformational changes that stabilize the signaling complex.

TNFRSF9 expression is tightly regulated in a spatiotemporal manner. It is minimally expressed in resting immune cells but is rapidly upregulated within 24–72 hours following T cell receptor (TCR) or B cell receptor (BCR) activation. This induction is mediated by transcription factors such as NFAT and NF-κB binding to promoter elements. Expression levels differ among immune cell subsets: highest and most sustained in CD8⁺ T cells, lower in CD4⁺ T cells, and inducible in natural killer (NK) cells, dendritic cells (DCs), and neutrophils. Pathologically, tumor-infiltrating lymphocytes (TILs) with high TNFRSF9 expression are associated with enhanced anti-tumor immune responses.

Biological Functions and Mechanisms

The primary ligand for TNFRSF9 is TNFSF9 (4-1BBL), a type II transmembrane protein predominantly expressed on activated antigen-presenting cells (APCs) such as DCs and macrophages. Interaction between 4-1BB and 4-1BBL triggers receptor trimerization and clustering, forming a stable signaling platform. This recruits TRAF proteins, mainly TRAF1 and TRAF2, activating two critical pathways: the canonical NF-κB pathway, which promotes degradation of IκBα and nuclear translocation of p50–RelA to drive transcription of survival genes (e.g., BCL2, BCL2L1, FLIP), and the PI3K–Akt–mTOR pathway, which enhances glucose uptake, protein synthesis, and metabolic adaptation, thereby promoting cellular proliferation and survival.

At the cellular level, TNFRSF9 signaling exerts multiple immunological effects. In T cells, it provides potent costimulatory signals that enhance CD8⁺ T cell cytotoxicity, increase perforin and granzyme B expression, prolong effector T cell survival, and support memory T cell differentiation. In CD4⁺ T cells, 4-1BB signaling can antagonize Treg-mediated suppression and promote Th1 responses. In NK cells, it enhances antibody-dependent cellular cytotoxicity (ADCC) and IFN-γ secretion, synergizing with monoclonal antibody therapies. Moreover, reverse signaling through 4-1BBL in DCs promotes maturation and upregulation of CD80/CD86, improving antigen presentation. Notably, 4-1BB signaling influences mitochondrial function via the AMPK-PGC1α axis, increasing mitochondrial biogenesis and oxidative phosphorylation, which enhances T cell metabolic fitness and persistence, particularly in chronic infection and tumor microenvironments.

Clinical Translation and Therapeutic Development

The potent costimulatory properties of TNFRSF9 have made it a focus for cancer immunotherapy. Several agonistic antibodies are under clinical evaluation. Urelumab (BMS-663513), the first humanized IgG4 agonist, demonstrated single-agent anti-tumor activity in a phase I trial (NCT00309023) but was limited by hepatotoxicity at higher dose, attributed to FcγR-independent crosslinking of liver-resident CD8⁺ T cells. Dose optimization (0.1 mg/kg Q3W) improved safety, achieving an ORR of 42% in Hodgkin lymphoma. Utomilumab (PF-05082566), an IgG2 antibody designed for reduced Fc receptor binding, showed minimal toxicity in phase I studies (NCT01307267) but limited single-agent efficacy. Combination with PD-1 blockade in refractory NSCLC enhanced efficacy.

Figure 1. Schematic representation of CD137+ T-cell activation as a result of priming by TAA-carrying activated APC. (Ugolini A, et al., 2021)

Emerging bispecific antibodies aim to enhance local agonist activity. APX601 (CD20x4-1BB) leverages tumor targeting to potentiate T cell activation, achieving an ORR of 36% without hepatotoxicity in phase I NHL trials (NCT02447367). Similarly, DuoBody®-CD40x4-1BB bridges DCs and T cells in solid tumors, enhancing immune synapse formation. In CAR-T therapy, the 4-1BB costimulatory domain has been integrated into CD19 CAR-T cells, with exogenous 4-1BB agonist treatment further expanding CAR-T persistence and improving complete remission rates in relapsed/refractory DLBCL models.

Challenges and Innovative Approaches

Despite the promising potential, TNFRSF9-targeted therapies face significant challenges. Dose-limiting hepatotoxicity, exemplified by Urelumab, reflects the risks of systemic immune activation. Mechanistically, off-tumor 4-1BB activation in liver-resident CD8⁺ T cells triggers cytokine release syndrome (CRS). Strategies to mitigate toxicity include conditionally activated antibodies, weakened Fc receptor-binding variants, and bispecific formats for tumor-restricted activation.

Another limitation is the lack of predictive biomarkers for response. Preliminary data suggest that pre-treatment tumor-infiltrating CD8⁺ T cells correlate with efficacy, but prospective validation is needed. The H_TNFRSF9 Reporter 293 cell line (GM-C04832) provides a standardized in vitro platform for quantifying 4-1BB signaling, accelerating antibody screening. Tumor-mediated immune evasion, via upregulation of checkpoints (PD-L1, VISTA) or secretion of suppressive factors (TGF-β, IL-10), further complicates treatment, highlighting the importance of rational combination strategies, including PD-1/PD-L1 inhibitors, chemotherapy- or radiotherapy-induced immunogenic cell death, and STING agonists to amplify type I interferon responses.

Reference

Claus C, Ferrara-Koller C, Klein C. The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy. MAbs. 2023 Jan-Dec;15(1):2167189.
Ugolini A, Nuti M. CD137+ T-Cells: Protagonists of the Immunotherapy Revolution. Cancers (Basel). 2021 Jan 26;13(3):456.

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