Regulation of the tumor immune microenvironment by the Hippo Pathway: Implications for cancer immunotherapy.

The tumor immune microenvironment (TIME) is a dynamic and complex ecosystem consisting of immune cells, stromal cells, and tumor cells. It plays a crucial role in shaping cancer progression and treatment outcomes. Notably, tumor-associated immune cells are key regulators within the TIME, influencing immune responses and therapeutic efficacy. The Hippo pathway is a critical signaling pathway involved in the TIME and cancer progression. In this review, we provide an overview of the Hippo pathway's role in the TIME, focusing on its interactions with immune cells and their implications in cancer biology and therapy. Specifically, we discuss the involvement of the Hippo pathway in regulating T-cell function, macrophage polarization, B-cell differentiation, MDSC activity, and dendritic cell-mediated immune responses. Furthermore, we explore its influence on PD-L1 expression in lymphocytes and its potential as a therapeutic target. While recent progress has been made in understanding the Hippo pathway's molecular mechanisms, challenges remain in deciphering its context-dependent effects in different cancers and identifying predictive biomarkers for targeted therapies. By elucidating the intricate crosstalk between the Hippo pathway and the TME, we aim to contribute to the development of innovative strategies for cancer treatment.

Comparisons of the immunological landscape of COVID-19 patients based on sex and disease severity by multi-omics analysis.

OBJECTIVE: To determine the differences in the immune response against SARS-CoV-2 infection of patients based on sex and disease severity. METHODS: We used an analytical framework of 382 transcriptional modules and multi-omics analyses to discriminate COVID-19 patients based on sex and disease severity. RESULTS: Male and female patients overexpressed modules related to the innate immune response. The expression of modules related to the adaptive immune response showed lower enrichment levels in males than females. Inflammation modules showed ascending overexpression in male and female patients, while a higher level was observed in severe female patients. Moderate female patients demonstrated significant overexpression to interferon, cytolytic lymphocyte, T & B cells, and erythrocytes modules. Moderate female patients showed a higher adaptive immune response than males matched group. Pathways involved in metabolism dysregulation and Hippo signaling were upregulated in females than in male patients. Females and moderate cases showed higher levels of metabolic dysregulation. CONCLUSIONS: The immune landscape in COVID-19 patients was noticeably different between the sexes, and these differences may highlight disease vulnerability in males. This study suggested that certain treatments that increase or decrease the immune responses to SARS-CoV-2 might be necessary for male and female patients at certain disease stages.

Integrated genomics point to immune vulnerabilities in pleural mesothelioma.

Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

Immuno-hippo: Research progress of the hippo pathway in autoimmune disease.

Extensive research in Drosophila and mammals has identified the core components of Hippo signaling, which controls gene expression. Studies of Drosophila have demonstrated the highly conserved Hippo pathway controls tissue homeostasis and organ size by regulating the balance between cell proliferation and apoptosis. Recent work has indicated a potential role of the Hippo pathway in regulating the immune system, which is the key player in autoimmune disease (AID). Therefore, the Hippo pathway may become a novel target for curing AID. Although the pivotal role of both the Hippo pathway in tumorigenesis has been thoroughly investigated, the role of it in AID is still poorly understood. Elucidating the role of Hippo signaling pathways in the activation and expression of specific molecules involved in immune regulation is important for understanding the pathogenesis of AID and exploring novel therapeutic targets. To aid in further research, this review describes the relationship between the Hippo pathway and inflammatory signals such as NF-κB and JAK-STAT, the function of the Hippo pathway in the formation and differentiation of immune cells, and the regulatory role of the Hippo pathway in AID.