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Analysis of CD8+ T cell of BCD mice

ABSTRACT: The gut microbiome has garnered attention as an effective target to boost immunity and improve cancer immunotherapy. We found that B cell defective (BCD) mice, such as µ membrane targeted deletion (µMT) and activation-induced cytidine deaminase (AID) knockouts (KO), have elevated anti-tumor immunity under specific-pathogen-free but not germ-free conditions. Microbial dysbiosis in these BCD mice enriched the type I interferon (IFN) signature in mucosal CD8+ T cells, resulting in upregulation of the type I IFN-inducible protein stem cells antigen-1 (Sca-1). Among CD8+ T cells, naïve cells predominantly circulate from the gut to periphery, and those that had migrated from the mLN to the periphery had significantly higher expression of Sca-1. The gut-educated Sca-1+ naïve subset is endowed with enhanced mitochondrial activity and anti-tumor effector potential. The heterogeneity and functional versatility of the systemic naïve CD8+ T cell compartment was revealed by single cell analysis and functional assays of CD8+ T cell subpopulations. These results indicate one of the potential mechanisms through which microbial dysbiosis regulates anti-tumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE155632 | GEO | 2023/08/03

REPOSITORIES: GEO

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Project description:Pancreatic cancer is the 3rd most prevalent cause of cancer related deaths in United states alone, with over 55000 patients being diagnosed in 2019 alone and nearly as many succumbing to it. Late detection, lack of effective therapy and poor understanding of pancreatic cancer systemically contributes to its poor survival statistics. Obesity and high caloric intake linked co-morbidities like type 2 diabetes (T2D) have been attributed as being risk factors for a number of cancers including pancreatic cancer. Studies on gut microbiome has shown that lifestyle factors as well as diet has a huge effect on the microbial flora of the gut. Further, modulation of gut microbiome has been seen to contribute to effects of intensive insulin therapy in mice on high fat diet. In another study, abnormal gut microbiota was reported to contribute to development of diabetes in Db/Db mice. Recent studies indicate that microbiome and microbial dysbiosis plays a role in not only the onset of disease but also in its outcome. In colorectal cancer, Fusobacterium has been reported to promote therapy resistance. Certain intra-tumoral bacteria have also been shown to elicit chemo-resistance by metabolizing anti-cancerous agents. In pancreatic cancer, studies on altered gut microbiome have been relatively recent. Microbial dysbiosis has been observed to be associated with pancreatic tumor progression. Modulation of microbiome has been shown to affect response to anti-PD1 therapy in this disease as well. However, most of the studies in pancreatic cancer and microbiome have remained focused om immune modulation. In the current study, we observed that in a T2D mouse model, the microbiome changed significantly as the hyperglycemia developed in these animals. Our results further showed that, tumors implanted in the T2D mice responded poorly to Gemcitabine/Paclitaxel (Gem/Pac) standard of care compared to those in the control group. A metabolomic reconstruction of the WGS of the gut microbiota further revealed that an enrichment of bacterial population involved in drug metabolism in the T2D group.

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Analysis of CD8+ T cell of BCD mice

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