Immunoregulatory properties of CD137-CD137 ligand axis in tumours and chronic inflammatory conditions

CD137 (4-1BB/TNFRSF9) is a member of the TNF receptor superfamily. CD137 expression is activation-dependent, and usually reported on T cells and NK cells. Its natural ligand is CD137 ligand (CD137L), mainly found on antigen-presenting cells (APC) such as monocytes, or dendritic cells. CD137-CD137L interaction will send a stimulatory signal to activate both interacting cells, thus enhancing the immune response. Hence, it is curious to detect CD137 on tumour cells and regulatory T cells (Treg), who mainly aim to suppress the immune functions. Hence, we aim to investigate how the CD137-CD137L can confer immunosuppression which is beneficial for tumour growth, or the maintenance of a chronic inflammatory condition. Because of RNA alternative splicing, soluble isoforms of CD137 (sCD137) that lack the cytoplasmic domain can be produced and secreted to the surrounding environment. In Paper I, we reveal that sCD137 is a marker of liver cirrhosis in patients suffering hepatitis C and alcohol-associated disease. sCD137 impairs type-1 and type-2 T cell response but maintain type-17 and regulatory T cell response. Thus, it helps maintain the chronic inflammation associated with cirrhosis. In paper II, we reveal how Tregs express more CD137 than conventional T cells (Tcon), use CD137 to form a complex with CD137L, internalize the complex and deplete CD137L on APC, in a process termed “trogocytosis”. This process does not require CD137 signaling because our modified truncated CD137 that lacks the cytoplasmic domain can still deplete CD137L. APC that have their CD137L depleted in the process are less able to co-stimulate T cells. In paper III, we study how the stimulation of CD137 on T cells can induce B7-H7 expression. B7-H7 is a ligand usually upregulated in cancers and associated with worse prognosis for a wide variety of cancers. On immune cells, B7-H7 is usually reported on APC. Our study reveals that B7-H7 can be induced on T cells to regulate T cell function and serve as a biomarker for exhausted T cells. In paper IV, using the nasopharyngeal carcinoma (NPC) model, we study why tumours are selected to express CD137. Besides using CD137 for trogocytosis to deplete CD137L from APC, tumour can also receive CD137 signaling to upregulate p38 MAPK pathway, secrete more Interleukin (IL)-8, and express LAMC2 to enhance their survival, invasion, and metastasis. IL-8 has been reported to be important to recruit other immunosuppressive cells into the tumour microenvironment, and LAMC2 is involved in the Epithelial-Mesenchymal Transformation (EMT) process. Learning from these mechanisms, in paper V, we devise a fusion protein PD-1-CD137L that masks PD-L1, a coinhibitory molecule, with CD137L, a costimulatory molecule. In effect, this converts the tumour microenvironment from cold to hot. Not only blocking PD-L1/PD-1 pathway, but this fusion protein also presents more CD137L in the tumour microenvironment, sequesters sCD137, inhibits trogocytosis and liberates existing CD137L to activate tumourspecific T cells. In conclusion, while CD137 has been exploited as target for immunotherapy (as seen in several clinical trials where agonistic anti-CD137 antibodies are used for cancer treatment), it can induce immunosuppression beneficial to tumour and chronic inflammation. Studying these mechanisms of action elucidate how we can improve future immunotherapy involving CD137 and similar receptors

Training Management Skills for First-line Managers : case: company X

First-line managers play an important role in a company’s success as they are significantly involved in the day-to-day operations, guiding the employees through certain courses of action to help them accomplish the organizational goals. In order to do so successfully, management skills such as planning, organizing, directing, and controlling are required from every first-line manager. Training programs for first-line managers can be difficult as such managers are a large population in a company, and very diverse in terms of educational backgrounds and working experience (e.g. experience in managerial jobs). Training first-line managers has become a task so mandatory that modern organizations today should pay more attention to. As a fully foreign-owned life insurer in Vietnam, Company X has such a huge sales force, including as many as 11,000 agents nationwide. Managing such a large number of employees requires especially proper management skills which are still lacking from most first-line managers. This stresses the utmost importance to provide them with training to ensure all the first-line managers possess sufficient and equal management skills. The purpose of this research was to find out the current situation of the first-line managers’ management skills in Company X, to understand the middle management’s expectations of the first-line managers in Company X, concerning their management skills, and to find ways how Company X should organize its management training programs to improve first the first-line managers’ management skills, and then their work performance. The research will be carried out using both the quantitative and the qualitative methods

Factors Affecting E-Commerce Customer Satisfaction in Hanoi, Vietnam

The escalating ubiquity and cost-effectiveness of internet facilities have precipitated a notable surge in the adoption of e-commerce among Vietnamese inhabitants, particularly those residing in urban areas. This research endeavours to enhance comprehension of factors affecting e-commerce customer satisfaction in Hanoi, Vietnam. A quantitative survey of this research was conducted in which online questionnaires were distributed to 382 respondents through social media. The amassed data underwent meticulous analysis utilizing Microsoft Excel. The findings of this investigation underscore that information quality, system quality, service quality and price simultaneously influence e-commerce customer satisfaction. Keywords: factors, e-commerce customers, satisfaction DOI: 10.7176/EJBM/16-2-03 Publication date:March 31st 202

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

IMMUNOREGULATORY PROPERTIES OF CD137-CD137 LIGAND AXIS IN TUMOURS AND CHRONIC INFLAMMATORY CONDITIONS

Ph.DDOCTOR OF PHILOSOPHY (NUSGS

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

10.3389/fimmu.2021.682627Frontiers in Immunology1268262

Destroy, what destroys you

10.1080/2162402X.2019.1685301OncoImmunology9011-

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

10.1002/JLB.2MR1119-224RJOURNAL OF LEUKOCYTE BIOLOGY1075731-73

Factors Affecting E-Commerce Customer Satisfaction in Hanoi, Vietnam

The escalating ubiquity and cost-effectiveness of internet facilities have precipitated a notable surge in the adoption of e-commerce among Vietnamese inhabitants, particularly those residing in urban areas. This research endeavours to enhance comprehension of factors affecting e-commerce customer satisfaction in Hanoi, Vietnam. A quantitative survey of this research was conducted in which online questionnaires were distributed to 382 respondents through social media. The amassed data underwent meticulous analysis utilizing Microsoft Excel. The findings of this investigation underscore that information quality, system quality, service quality and price simultaneously influence e-commerce customer satisfaction. Keywords: factors, e-commerce customers, satisfaction DOI: 10.7176/JESD/15-5-01 Publication date: April 30th 202

First record for Asemonea tenuipes in Vietnam (Araneae: Salticidae: Asemoneinae)

Tam, Truong Van, Nhan, Vo Hieu, Khang, Luu Vinh (2020): First record for Asemonea tenuipes in Vietnam (Araneae: Salticidae: Asemoneinae). Peckhamia 227 (1): 1-2, DOI: http://doi.org/10.5281/zenodo.509345