The anti-tumorigenic role of CARD9 signaling cascade in conventional dendritic cells in colitis-associated colon cancer

Küntzel, Vanessa (2024): The anti-tumorigenic role of CARD9 signaling cascade in conventional dendritic cells in colitis-associated colon cancer. Dissertation, LMU München: Medizinische Fakultät

Abstract

Colorectal cancer (CRC) is the third most common type of cancer worldwide, with around 2 million new cases yearly, and the second most common cause of overall cancer mor-tality. A common risk factor for developing CRC is inflammatory bowel disease (IBD), marked by a chronic inflammatory process within the intestinal compartment. Genome-wide association studies (GWAS) identified Card9 polymorphisms associated with an increased risk of colon cancer development. CARD9 acts in a complex with BCL10-MALT1 and is exclusively expressed in myeloid cells, like macrophages, dendritic cells (DCs), and Neutrophils. Previous studies on the role of CARD9 in tumor development have shown contradicting results regarding tumor development and identified signaling mechanisms for CARD9 independently of BCL10 and MALT1. This study aimed to char-acterize the role of CARD9-BCL10-MALT1 signaling in DCs under homeostatic condi-tions, acute inflammation, and colitis-associated cancer. DCs belong to the innate im-mune system and play a crucial role in antigen uptake, processing, and presentation to T cells. DCs can be split into two main subsets, conventional DC1 (cDC1) and cDC2, each specialized for the induction of cytotoxic CD8 T cells or CD4 T helper cells, respectively. CARD9 signaling was abrogated in cDCs by deleting its interaction partner BCL10 or the deletion of upstream SYK kinase using the Clec9a-cre mouse model combined with floxed alleles of the targeted gene. Deletion of both proteins had no impact on the devel-opment of cDCs, particularly in the intestinal compartment. However, transcriptional pro-filing of BCL10 deficient intestinal cDCs revealed reduced mitochondrial biogenesis-related gene expression, specifically in OXPHOS. Presumably caused by decreased mTOR and Myc signaling, indicating that the deletion of BCL10 likely affects the early activation or maturation of cDCs. In contrast, the deletion of SYK in cDCs did not show differences in metabolic signaling. Further, cDC-specific deletion of BCL10, but not SYK, led to a reduced Th17 induction in the colon of these mice. However, lower Th17 pres-ence and altered metabolism of BCL10 deficient cDCs had no impact on acute colitis. Similarly, the Clec9acre/+Sykfl/fl mice showed no alterations in acute colitis. Nonetheless, increased tumor development could be observed in cDC-specific BCL10 deficient mice upon chronic colitis. This increased tumor development could be traced to a defect in anti-tumor immunity when BCL10 is deleted in cDCs. Tumor-infiltrating T cells showed a reduction of unconventional γδ T cells, increased tolerogenic CD4 T cells, and less cytotoxicity within the tumor environment. If this protective effect on BCL10 in cDCs is mediated via SYK signaling is part of future investigations.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: CARD9, Colon cancer, Dendritic cells
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 18. April 2024
• 1. Bericht­erstatter:in: Schraml-Schotta, Barbara