Soluble CD137 is a novel serum marker of liver cirrhosis in patients with hepatitis C and alcohol-associated disease etiology.

Defective T-cell functions play a role in the persistence of HCV infection. Activated T cells express CD137, which costimulates antivirus T-cell responses, and this activity is antagonized by soluble CD137 (sCD137). Here, we show that in sera of 81 patients with chronic HCV, sCD137 levels did not correlate with measures of viral infection, and did not decline after virus eradication using direct-acting antivirals. Thus, serum sCD137 was similar in patients infected with HCV and in uninfected controls. Of note, in HCV patients with liver cirrhosis and patients with mostly alcohol-associated liver cirrhosis, sCD137 was increased. A negative association of sCD137 and albumin existed in both cohorts. sCD137 concentrations were similar in hepatic and portal vein blood excluding the liver as the origin of higher levels. Recombinant sCD137 reduced Th1 and Th2 but not Th17 cell polarization in vitro, and accordingly lowered IFN-γ, TNF, and IL-13 in cell media. Serum sCD137 is associated with inflammatory states, and positively correlated with serum TNF in cirrhotic HCV patients following virus eradication. Our study argues against a role of sCD137 in HCV infection and suggests a function of sCD137 in liver cirrhosis, which yet has to be defined.

Epstein-Barr virus-induced ectopic CD137 expression helps nasopharyngeal carcinoma to escape immune surveillance and enables targeting by chimeric antigen receptors.

Non-keratinizing nasopharyngeal carcinoma (NPC) is a malignancy with a poor prognosis for relapsing patients and those with metastatic disease. Here, we identify a novel disease mechanism of NPC which may be its Achilles' heel that makes it susceptible to immunotherapy. CD137 is a potent costimulatory receptor on activated T cells, and CD137 agonists strongly enhance anti-tumor immune responses. A negative feedback mechanism prevents overstimulation by transferring CD137 from T cells to CD137 ligand (CD137L)-expressing antigen presenting cells (APC) during cognate interaction, upon which the CD137-CD137L complex is internalized and degraded. We found ectopic expression of CD137 on 42 of 122 (34.4%) NPC cases, and that CD137 is induced by the Epstein-Barr virus latent membrane protein (LMP) 1. CD137 expression enables NPC to hijack the inbuilt negative feedback mechanism to downregulate the costimulatory CD137L on APC, facilitating its escape from immune surveillance. Further, the ectopically expressed CD137 signals into NPC cells via the p38-MAPK pathway, and induces the expression of IL-6, IL-8 and Laminin γ2. As much as ectopic CD137 expression may support the growth and spread of NPC, it may be a target for its immunotherapeutic elimination. Natural killer cells that express a CD137-specific chimeric antigen receptor induce death in CD137+ NPC cells, in vitro, and in vivo in a murine xenograft model. These data identify a novel immune escape mechanism of NPC, and lay the foundation for an urgently needed immunotherapeutic approach for NPC.

Eco-friendly fashion among generation Z: Mixed-methods study on price value image, customer fulfillment, and pro-environmental behavior.

Raising environmental awareness and product development are two separate and costly investments that many small and medium-sized fashion businesses cannot afford to achieve sustainability. Therefore, there is a need to determine which factors exert a more significant impact on consumer loyalty and purchase intention toward eco-friendly fashions. Thus, this study employs a mixed-methods approach with thematic analysis and the SEM-PLS technique to research how Vietnamese Gen Z's perceptions of product-service quality, environmental awareness, and pro-environmental behavior influence their purchase intention and loyalty toward eco-friendly fashion products. Most interviewees acknowledged that they primarily gained knowledge about eco-friendly fashion through social media platforms. The qualitative results further showed that their knowledge of and attitudes toward eco-friendly fashion practices were insufficient to convince young customers to afford eco-friendly fashion products. The SEM-PLS results of 313 participants show that while customers' perceived behavioral control plays a more significant role in stimulating purchase intention, only product-service quality factors impact loyalty. Hence, this study suggests that businesses should prioritize improving service and product quality rather than funding green marketing when targeting Vietnamese Gen Z in case of financial constraints. Government should prioritize financial and technological support for fashion firms to develop high-quality eco-friendly fashion to ensure the product availability.

B7-H7 Is Inducible on T Cells to Regulate Their Immune Response and Serves as a Marker for Exhaustion.

The discovery of immune checkpoints highlights the complexity of T cell signalling during an immune response. Upon activation, T cells express several molecules to regulate their function and to prevent overactivation. B7 homolog 7 (B7-H7) is expressed in tumours and associated with a worse prognosis. However, conflicting data regarding its function suggest that it can be both stimulatory and inhibitory. In this study we report that B7-H7 is also expressed on T cells upon cross-linking of CD3 and CD28 and that additional stimulation via CD137 further enhances the expression of B7-H7. B7-H7 is preferentially expressed on exhausted Th1 and Tc1 cells with an impaired secretion of TNF-α and IFN-γ. Blockade of B7-H7 with its natural receptor, recombinant CD28H, enhances T cell proliferation and activation. Thus, B7-H7 represents another target for immunotherapy and a biomarker to select for active effector T cells with relevance for adoptive cell transfer therapy.

Regulatory T Cells Inhibit T Cell Activity by Downregulating CD137 Ligand via CD137 Trogocytosis.

CD137 is a costimulatory molecule expressed on activated T cells. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), which use the CD137-CD137L system to enhance immune responses. It was, therefore, surprising to discover CD137 expression on regulatory T cells (Treg). The function of CD137 in Treg are controversial. While some studies report that CD137 signalling converts Treg to effector T cells (Teff), other studies find that CD137-expressing Treg display a stronger inhibitory activity than CD137- Treg. Here, we describe that CD137 on Treg binds to CD137L on APC, upon which one of the two molecules is transferred via trogocytosis to the other cell, where CD137-CD137L forms a complex that is internalized and deprives APC of the immune-stimulatory CD137L. Truncated forms of CD137 that lack the cytoplasmic domain of CD137 are also able to downregulate CD137L, demonstrating that CD137 signalling is not required. Comparable data have been obtained with human and murine cells, indicating that this mechanism is evolutionarily conserved. These data describe trogocytosis of CD137 and CD137L as a new mechanism employed by Treg to control immune responses by downregulating the immunostimulatory CD137L on APC.

Destroy, what destroys you.

New evidence indicates the importance of CD137 for controlling Epstein-Barr virus (EBV) infections. (1) Mutations in CD137 predispose to EBV-associated diseases. (2) EBV induces ectopic CD137 expression, thereby activating a negative feed-back regulation and reducing T cell costimulation. These findings suggest CD137 agonists as new treatments for EBV-associated diseases.

The relevance of soluble CD137 in the regulation of immune responses and for immunotherapeutic intervention.

CD137 is a potent costimulatory receptor. Several agonistic anti-CD137 antibodies are currently in clinical trials for tumor immunotherapy. Soluble forms of CD137 (sCD137) are generated by differential splicing and antagonize the activities of membrane-bound CD137 (mCD137) and of therapeutic CD137 agonists. sCD137 is found in sera of patients suffering from autoimmune diseases where it is a natural regulator of immune responses, and which has therapeutic potential for immune-mediated diseases. This review summarizes the current knowledge on sCD137, highlights its potential role in immunotherapy against cancer and in autoimmune diseases, and presents important issues to be addressed by future research.