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      B cell immune profiles in dysbiotic vermiform appendixes of pancreatic cancer patients

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          Abstract

          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 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.

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          Most cited references49

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          Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes

          Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5-years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short and long-term survival (STS, LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas/Streptomyces/Saccharopolyspora/Bacillus clausii) highly predictive of long term survivorship in both discovery and validation cohorts. Through human-into-mice Fecal Microbiota Transplantation (FMT) experiments from STS, LTS or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease. The distinct tumor microbiome from pancreatic cancer long-term survivors can be used to predict PDAC survival in humans, and transfer of long-term survivor gut microbiomes can alter the tumor microbiome and tumor growth in mouse models.
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            B Cell Responses: Cell Interaction Dynamics and Decisions

            B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here we review current understanding of how B cell responses are initiated, the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells, and how each path impacts antibody diversity, selectivity and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses, and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.
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              The Fungal Mycobiome Promotes Pancreatic Oncogenesis via MBL Activation

              Bacterial dysbiosis has emerged as an accomplice to carcinogenesis in malignancies such as colon and liver cancer, and we have recently implicated the microbiome in the pathogenesis of pancreatic ductal adenocarcinoma (PDA) 1 . However, the mycobiome has not been clearly implicated in tumorigenesis. We found that fungi migrate from the gut lumen to the pancreas. PDA tumors harbored a ~3000-fold increase in fungi compared to normal pancreas in both mice and humans. The composition of the PDA mycobiome was distinct from that of gut or normal pancreas based on alpha and beta diversity indices. Specifically, the fungal community infiltrating PDA tumors was markedly enriched for Malassezia in both mice and humans. Fungal ablation was tumor-protective in slowly progressive and invasive models of PDA whereas repopulation with Malassezia – but not Candida, Saccharomyces, or Aspergillus – accelerated oncogenesis. In parallel, we discovered that ligation of mannose-binding lectin (MBL), which binds fungal wall glycans to activate the complement cascade, was required for oncogenic progression whereas MBL or C3 deletion in the extra-tumoral compartment or C3aR knockdown in tumor cells were protective. Further, reprogramming of the mycobiome did not alter PDA progression in Mbl or C3 deficient mice. Collectively, our work shows that pathogenic fungi promote PDA by driving the complement cascade via MBL activation.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                10 November 2023
                2023
                : 14
                : 1230306
                Affiliations
                [1] 1 Department of Pulmonary Medicine, Erasmus MC Cancer Institute , Rotterdam, Netherlands
                [2] 2 Department of Surgery, Erasmus MC Cancer Institute , Rotterdam, Netherlands
                [3] 3 Department of Surgery, Reinier de Graaf Hospital , Delft, Netherlands
                [4] 4 Department of Surgery, IJsselland Hospital , Capelle aan den IJssel, Netherlands
                [5] 5 Department of Pathology, Pathan BV , Rotterdam, Netherlands
                [6] 6 Department of Pathology, Erasmus University Medical Center , Rotterdam, Netherlands
                [7] 7 Department of Pathology, Leiden University Medical Center , Leiden, Netherlands
                [8] 8 Department of Immunology, Erasmus University Medical Center , Rotterdam, Netherlands
                Author notes

                Edited by: Tomas Castro-Dopico, The Francis Crick Institute, United Kingdom

                Reviewed by: Ola Grimsholm, Medical University of Vienna, Austria; Ayca Sayi Yazgan, Istanbul Technical University, Türkiye

                *Correspondence: Casper H.J. van Eijck, c.vaneijck@ 123456erasmusmc.nl
                Article
                10.3389/fimmu.2023.1230306
                10667699
                516810e4-c57a-4d09-afdb-3f1f30e83bd1
                Copyright © 2023 Vietsch, Latifi, Verheij, van der Oost, de Wilde, Haen, van den Boom, Koerkamp, Doornebosch, van Verschuer, Ooms, Mohammad, Willemsen, Aerts, Krog, de Miranda, van den Bosch, Mueller, Katsikis and van Eijck

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 May 2023
                : 18 October 2023
                Page count
                Figures: 5, Tables: 3, Equations: 0, References: 49, Pages: 15, Words: 9314
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was funded by the Survival with Pancreatic Cancer Foundation (Support Casper).
                Categories
                Immunology
                Original Research
                Custom metadata
                B Cell Biology

                Immunology
                vermiform appendix,pancreatic cancer,colon cancer,mucosal b cells,gut associated lymphoid tissue,gut microbiome,hla-g,hla-dr

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