TNFSF8

Official Full Name

TNF superfamily member 8

Organism

Homo sapiens

GeneID

944

Background

The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This cytokine is a ligand for TNFRSF8/CD30, which is a cell surface antigen and a marker for Hodgkin lymphoma and related hematologic malignancies. The engagement of this cytokine expressed on B cell surface plays an inhibitory role in modulating Ig class switch. This cytokine was shown to enhance cell proliferation of some lymphoma cell lines, while to induce cell death and reduce cell proliferation of other lymphoma cell lines. The pleiotropic biologic activities of this cytokine on different CD30+ lymphoma cell lines may play a pathophysiologic role in Hodgkin's and some non-Hodgkin's lymphomas. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

Synonyms

CD153; CD30L; CD30LG; TNLG3A;

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Detailed Information

The TNFSF8 gene encodes Tumor Necrosis Factor Superfamily Member 8, more commonly known in immunology as CD30 Ligand (CD30L). CD30L is a type II transmembrane protein that primarily functions as a trimer, existing either as a membrane-bound ligand on the cell surface or as a soluble form released via proteolytic cleavage. The TNFSF8 gene is located on human chromosome 9q32. CD30L expression is largely restricted to activated T cells, B cells, natural killer cells, and monocytes/macrophages. Its only known receptor, CD30, is a type I transmembrane protein belonging to the TNF receptor superfamily. CD30 exhibits highly characteristic expression: it is minimally expressed on resting T and B cells but is significantly upregulated in specific activated T and B cell subsets. Clinically, CD30 is a hallmark surface antigen for certain hematologic malignancies, including classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL), making the CD30L-CD30 axis a long-standing focus in lymphoma biology.

Biological Significance

TNFSF8/CD30L demonstrates notable functional diversity and context dependency. Through interaction with CD30, it plays complex roles in immune regulation and lymphoma pathophysiology. In normal immune responses, the CD30L-CD30 signaling pathway is a critical T cell co-stimulatory axis. Engagement of CD30L on antigen-presenting cells with CD30 on naïve T cells promotes T cell clonal expansion and differentiation, particularly favoring Th2-type cytokine production. The pathway also regulates B cell function; CD30L engagement on B cells can inhibit class-switch recombination, reflecting its fine-tuning role in humoral immunity.

In CD30-positive lymphoma cells, CD30L-CD30 signaling exhibits a paradoxical duality. In some lymphoma cells, CD30 activation transmits strong survival and proliferation signals, consistent with its co-stimulatory role in normal T cells, thereby promoting tumor expansion. Conversely, in other lymphoma cell models, the same CD30 activation signal can induce cell cycle arrest and programmed cell death. This duality-pro-survival and pro-apoptotic-highlights the highly cell-context-dependent outcome of this signaling axis, influenced by intracellular signaling networks, coexisting receptors, and transcription factor expression. This multifaceted behavior underscores the CD30L-CD30 axis as a critical determinant in the pathophysiology of cHL and related non-Hodgkin lymphomas, capable of both driving and restraining tumor progression depending on the cellular context.

Figure 1. CD30 signaling via trogocytosis. (Nakashima M, et al., 2023)

Clinical Relevance

The clinical significance of the TNFSF8/CD30L-CD30 pathway centers almost entirely on its role as a therapeutic target in lymphomas. Due to CD30's high specificity and abundance on tumor cells in cHL and systemic ALCL, it is an ideal target for therapy. The most successful example is Brentuximab Vedotin (BV), an antibody-drug conjugate (ADC) composed of a CD30-targeting monoclonal antibody, a cleavable linker, and a potent microtubule-disrupting cytotoxin. BV binds specifically to CD30 on tumor cells, undergoes internalization, and releases the cytotoxic payload in lysosomes, achieving targeted killing of CD30-positive tumor cells while minimizing systemic toxicity. BV has demonstrated transformative efficacy in relapsed/refractory cHL and sALCL and has been integrated into frontline treatment regimens.

Beyond ADCs, other therapeutic strategies targeting this pathway are being explored. Agonistic antibodies that mimic CD30L and aim to trigger CD30-mediated apoptotic signaling represent a potential approach, though efficacy is highly dependent on the tumor's intrinsic signaling context. Additionally, soluble CD30 levels are being investigated as biomarkers for disease activity and prognosis. Clinical challenges include the development of resistance, potentially through downregulation of CD30 expression or adaptive alterations in intracellular signaling. Understanding the complex downstream signaling network is therefore critical for devising strategies to overcome resistance. Combination therapies, such as CD30-targeted agents with PD-1 inhibitors, are also under active investigation to enhance antitumor efficacy.

In summary, the TNFSF8/CD30L-CD30 axis is not only a hallmark of lymphoma biology but also a paradigm of targeted therapy and translational immunotherapy.

References

Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363(19):1812-1821.
Oflazoglu E, Grewal IS, Gerber H. Targeting CD30/CD30L in oncology and autoimmune and inflammatory diseases. Adv Exp Med Biol. 2009;647:174-85.
Marín ND, García LF. The role of CD30 and CD153 (CD30L) in the anti-mycobacterial immune response. Tuberculosis (Edinb). 2017 Jan;102:8-15.
Nakashima M, Uchimaru K. CD30 Expression and Its Functions during the Disease Progression of Adult T-Cell Leukemia/Lymphoma. Int J Mol Sci. 2023 May 13;24(10):8731.

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