Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both... Show morePancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with Klebsiella pneumoniae, Bifidobacterium animalis, and Adlercreutzia equolifaciens, while certain commensals are depleted. Our findings may suggest impaired B cell function within the GALT of PDAC patients, which could potentially be linked to microbial dysbiosis. Additional investigations are imperative to validate our observations and explore these potential targets of future therapies. Show less
Weerts, M.J.A.; Lanko, K.; Guzman-Vega, F.J.; Jackson, A.; Ramakrishnan, R.; Cardona-Londono, K.J.; ... ; Genomics England Res 2021
Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features... Show morePurpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome. Show less
Tio, D.; Kasiem, F.R.; Willemsen, M.; Doorn, R. van; Werf, N. van der; Hoekzema, R.; ... ; Bekkenk, M.W. 2019
The cancer/testis antigen (CTA) family is a group of antigens whose expression is restricted to male germline cells of the testis and various malignancies. This expression pattern makes this group... Show moreThe cancer/testis antigen (CTA) family is a group of antigens whose expression is restricted to male germline cells of the testis and various malignancies. This expression pattern makes this group of antigens potential targets for immunotherapy. The aim of this study was to create an overview of CTA expressed by melanoma cells at mRNA and protein level. A systematic literature search was performed in Medline (PubMed) and Embase from inception up to and including February 2018. Studies were screened for eligibility by two independent reviewers. A total of 65 full-text articles were included in the final analysis. A total of 48 CTA have been studied in melanoma. Various CTA show different expression rates in primary and metastatic tumours. Of the 48 CTA, the most studied were MAGE-A3, MAGE-A1, NY-ESO-1, MAGE-A4, SSX2, MAGE-A2, MAGE-C1/CT7, SSX1, MAGE-C2/ CT10 and MAGE-A12. On average, MAGE-A3 mRNA is present in 36% of primary tumours, whereas metastatic tumours have an expression rate of 55-81%. The same applies to the protein expression rate of MAGE-A3 in primary tumours, which is reported to be at 15-37%, whereas metastatic tumours have a higher expression rate of 25-70%. This trend of increased expression in metastases compared with primary tumours is observed with MAGE-A1, MAGE-A2, MAGE-A4, MAGE-A12 and NY-ESO-1. Many CTA are expressed on melanoma. This review provides an overview of the expression frequency of CTAs in melanoma and may aid in identifying CTA as the therapeutic target for immunotherapy. Copyright (c) 2019 Wolters Kluwer Health, Inc. All rights reserved. Show less
