HVEM in acute lymphocytic leukemia facilitates tumour immune escape by inhibiting CD8+ T cell function.

PURPOSE: Leukaemia remains a major contributor to global mortality, representing a significant health risk for a substantial number of cancer patients. Despite notable advancements in the field, existing treatments frequently exhibit limited efficacy or recurrence. Here, we explored the potential of abolishing HVEM (herpes virus entry mediator, TNFRSF14) expression in tumours as an effective approach to treat acute lymphoblastic leukaemia (ALL) and prevent its recurrence. METHODS: The clinical correlations between HVEM and leukaemia were revealed by public data analysis. HVEM knockout (KO) murine T cell lymphoblastic leukaemia cell line EL4 were generated using CRISPR-Cas9 technology, and syngeneic subcutaneous tumour models were established to investigate the in vivo function of HVEM. Immunohistochemistry (IHC), RNA-seq and flow cytometry were used to analyse the tumour immune microenvironment (TIME) and tumour draining lymph nodes (dLNs). Immune functions were investigated by depletion of immune subsets in vivo and T cell functional assays in vitro. The HVEM mutant EL4 cell lines were constructed to investigate the functional domain responsible for immune escape. RESULTS: According to public databases, HVEM is highly expressed in patients with ALL and acute myeloid leukemia (AML) and is negatively correlated with patient prognosis. Genetic deletion of HVEM in EL4 cells markedly inhibited tumour progression and prolonged the survival of tumour-bearing mice. Our experiments proved that HVEM exerted its immunosuppressive effect by inhibiting antitumour function of CD8+ T cell through CRD1 domain both in vivo and in vitro. Additionally, we identified a combination therapy capable of completely eradicating ALL tumours, which induces immune memory toward tumour protection. CONCLUSIONS: Our study reveals the potential mechanisms by which HVEM facilitates ALL progression, and highlights HVEM as a promising target for clinical applications in relapsed ALL therapy.

Notch Signaling Regulates the Function and Phenotype of Dendritic Cells in Helicobacter pylori Infection.

Notch signaling manipulates the function and phenotype of dendritic cells (DCs), as well as the interaction between DCs and CD4+ T cells. However, the role of Notch signaling in Helicobacter pylori (H. pylori) infection remains elusive. Murine bone marrow-derived dendritic cells (BMDCs) were pretreated in the absence or presence of Notch signaling inhibitor DAPT prior to H. pylori stimulation and the levels of Notch components, cytokines and surface markers as well as the differentiation of CD4+ T cells in co-culture were measured using quantitative real-time PCR (qRT-PCR), Western blot, enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Compared with the control, the mRNA expression of all Notch receptors and Notch ligands Dll4 and Jagged1 was up-regulated in H. pylori-stimulated BMDCs. The blockade of Notch signaling by DAPT influenced the production of IL-1ß and IL-10 in H. pylori-pulsed BMDCs, and reduced the expression of Notch1, Notch3, Notch4, Dll1, Dll3 and Jagged2. In addition, DAPT pretreatment decreased the expression of maturation markers CD80, CD83, CD86, and major histocompatibility complex class II (MHC-II) of BMDCs, and further skewed Th17/Treg balance toward Treg. Notch signaling regulates the function and phenotype of DCs, thus mediating the differentiation of CD4+ T cells during H. pylori infection.

FAP is a prognostic marker, but not a viable therapeutic target for clinical translation in HNSCC.

PURPOSE: PD-1 targeted immunotherapy has imparted a survival benefit to advanced head and neck squamous cell carcinoma (HNSCC), but less than 20% patients produce a durable response to this therapy. Here we aimed to investigate the potential biomarkers for predicting the clinical outcome and resistance to PD-1 targeted immunotherapy in HNSCC patients, and to examine the involvement of FAP+ cancer-associated fibroblasts (CAFs). METHODS: Bioinformatics methods were applied to analyze multiple datasets and explore the role of PD-1 and FAP in HNSCC. Immunohistochemistry was used to detect the expression of FAP protein. Fap gene knockout mice (Fap-/-) and L929 cells with different levels of Fap overexpression (L929-Fap-Low/High) were established to demonstrate the role of FAP+ CAFs in tumor development and immune checkpoint blockade (ICB) resistance. RESULTS: The expression level of PD-1 gene was positively correlated with better overall survival and therapeutic response to PD-1 blockade in HNSCC, but not all tumors with high expression of both PD-1 and PD-L1 were responsive. Moreover, FAP gene was overexpressed in pan-cancer tissues, and could serve as a prognostic biomarker for several cancers, including HNSCC. However, FAP protein was undetectable in mouse MTCQ1 tumors and barely expressed in human HNSCC tumors. Furthermore, FAP+ CAFs did not promote tumor growth or enhance the resistance to PD-1 inhibitor treatment. CONCLUSION: Although FAP+ CAFs have attracted increasing attention for their role in cancer, the feasibility and efficacy of FAP-targeting therapies for HNSCC remain doubtful.

Improved sensitivity and positive predictive value of contrast-enhanced intraoperative ultrasound in colorectal cancer liver metastasis: a systematic review and meta-analysis.

Background: Surgery is an effective treatment for improving the survival rate of patients with colorectal cancer liver metastases (CRLM). However, accurately determining the resection margin of liver lesions during surgery remains challenging. Therefore, this study aimed to evaluate the sensitivity and predictive value of intraoperative contrast-enhanced ultrasound (CE-IOUS) in CRLM patients undergoing surgery. Methods: We performed a literature search of the PubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu databases using the following search terms: metastatic liver cancer, colorectal cancer, sensitivity, contrast-enhanced intraoperative ultrasound, CE-IOUS, colorectal liver metastases, and CRLM. The search period was set from the date of establishment of the database to September 2021. Quality assessment of diagnostic accuracy studies 2 (QUADAS-2) recommended by the Cochrane Collaboration was used to assess the methodological quality of the included studies, and network meta-analysis was performed using Stata 15.0 software. Results: A total of 10 articles met the inclusion criteria. The meta-analysis results showed that the overall sensitivity and specificity of CE-IOUS were 0.96 [95% confidence interval (CI), 0.95-0.97] and 0.75 (95% CI, 0.70-0.80), respectively. The overall sensitivity and specificity of IOUS were 0.84 (95% CI, 0.82-0.86) and 0.82 (95% CI, 0.77-0.87), respectively. The area under the summary receiving operating characteristic (SROC) curves (AUCs) of CE-IOUS and IOUS were 0.9753 and 0.8590, respectively. The odds ratio (OR) and 95% CI of CE-IOUS changed the surgical margin were 0.205 and 0.071-0.465, P=0.000, the difference was statistically significant. Discussion: Based on the results of this meta-analysis, CE-IOUS improved the sensitivity and predictive value of CRLM detection compared with IOUS, and is more suitable for intraoperative planning of surgical margins. At present, it is the most sensitive imaging method available, and is recommended for use during liver resection to provide doctors with more reliable information during surgery.