Cancer and the Microbiome最新文献

{"title":"Abstract A02: Gut microbiome controls growth of liver tumors","authors":"Chi Ma, Miaojun Han, B. Heinrich, Qiong Fu, Qian-fei Zhang, X. Wang, G. Trinchieri, T. Greten","doi":"10.1158/2326-6074.TUMIMM17-A02","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A02","url":null,"abstract":"Aim: The gut microbiome can modify tumor immunity and has been suggested to be involved in the development and growth of liver cancer as well as metastasis in the liver. However, it remains unknown how the gut microbiome controls hepatic immune responses. This study was designed to exam the effect of the gut microbiome on liver antitumor immunity, and to study potential mechanism. Experimental Procedure: An antibiotic cocktail containing 0.5g/L vancomycin, 0.5 g/L neomycin and 0.6 g/L primaxin in drinking water was given to reduce mouse gut microbiota. Control mice were kept on regular water. EL4 thymoma cells were injected s.c. to induces spontaneous liver metastasis. B16 melanoma and CT26 colon cancer cells were injected intrasplenically to form liver metastasis. Lung metastasis was induced by tail injection of tumor cells. Spontaneous hepatocellular carcinomas were studied in TRE-MYC mice. Gut bacteria and metabolic studies were performed. Results: Antibiotic cocktail efficiently depleted gut bacteria. Removing gut commensal bacteria did not affect the growth of primary s.c. EL4 tumors, but impaired formation of liver metastasis in different models. The inhibitory effect on liver metastasis by removing gut microbiome was found after intrasplenic injection of tumor cells to form liver metastasis using both B16 melanoma and CT26 colon cancer tumor cells as well as in TRE-MYC mice. Interestingly, formation of lung metastasis caused by tail vein injection of B16 cells was not impaired by antibiotics treatment, suggesting a liver specific effect. The inhibition of liver metastasis by antibiotic treatment was absent in Rag1 knockout mice, suggesting that the observed mechanism is mediated by the adaptive immune system. A detailed mechanism how the gut microbiome causes metabolic liver changes and thereby growth of liver tumors will be presented. Conclusion: Our results suggest that the gut microbiome affects the liver immune microenvironment and modulates antitumor immunity Citation Format: Chi Ma, Miaojun Han, Bernd Heinrich, Qiong Fu, Qianfei Zhang, Xin W. Wang, Giorgio Trinchieri, Tim Greten. Gut microbiome controls growth of liver tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A02.","PeriodicalId":309751,"journal":{"name":"Cancer and the Microbiome","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130547563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A04: Microbial and immunologic characterization of gastroesophageal tissue biopsy samples: A multiparametric analysis","authors":"Chao-peng Zhang, P. Thakkar, F. Schnoll-Sussman, Bridget McClure, Michelle Bigg, Gregory F. Sonnenberg, D. Betel, M. Shah","doi":"10.1158/2326-6074.TUMIMM17-A04","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A04","url":null,"abstract":"Gastric cancer carcinogenesis is associated with chronic inflammation, most commonly the result of Helicobacter pylori chronic infection in the stomach antrum. The development of gastric cancer in the context of chronic H. pylori infection is multifactorial, encompassing both bacterial factors and the altered immune microenvironment. However, a comprehensive analysis of the relation between inflammation and host microbial population in patient tissue samples has not previously been explored. We proposed an unbiased study to evaluate the relationships among microbiome composition, host immune response and genomic characterization from next-generation sequencing of gastric biopsy samples. Patients undergoing upper endoscopy without chronic inflammatory disease or chronic NSAID use were eligible for participation. Endoscopic biopsies from gastric fundus, body, and antrum were collected from patients with active H. pylori infection (n=21), prior infection (n=22) and no prior infection (n=26), and were sequenced at 10X to 30X coverage. In total, 77 gastric biopsies from 69 patients were freshly frozen for whole genome sequencing (WGS) and transcriptome (RNASeq) analysis. Detecting the microbiome from human biopsy sequencing data directly is challenging due to the low microbial content. A novel computational pipeline was developed to address this problem specifically (Zhang et al., Genome Biology 2015). A robust H. pylori signal was detected in samples from clinically verified H. pylori infected patients, and the results were further validated by qPCR. In our analysis population, in addition to identification of H. pylori, several bacteria associated with other cancers were also detected in several biopsy samples, such as Prevotella melaninogenica, Veillonella parvula and Fusobacterium nucleatum. H. pylori infection was associated with reduced microbial biodiversity compared to prior infection or control tissue (p=0.02). H. pylori active infection samples have a distinct non-H. pylori microbiome compared to prior infection and control samples. We also identified 5 patients with prior infection and 1 control patient with occult H. pylori infection (e.g., asymptomatic patients). To characterize the immune infiltration in the mucosal biopsy samples, we developed a 176-gene panel, collected from multiple published studies, to define the immune signatures. The expression profile of this immune gene panel was used evaluate the immune infiltration levels of multiple immune cell types. The result of unsupervised clustering revealed a much higher immune infiltration in H. pylori positive samples compared to uninfected samples, especially for CD8+, Th2 and Th17 cell populations. Two orthogonal experimental essays (ELISA and Flow Cytometry) were performed independently to verify the results. ELISA results confirmed the RNAseq-based expression profiling of inflammatory cytokines such as GRO, IL8, TNFa and SCD40L. Importantly, in 2 patients with prior H. pylori inf","PeriodicalId":309751,"journal":{"name":"Cancer and the Microbiome","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128616107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PR06: Drugging the human microbiome for combination with tumor immunotherapy","authors":"D. N. Cook, J. Peled, M. Brink, L. Jayaraman","doi":"10.1158/2326-6074.TUMIMM17-PR06","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-PR06","url":null,"abstract":"The human gut microbiome is a diverse, dynamic, and complex ecosystem that modulates host processes including metabolism, inflammation, and cellular and humoral immune responses. Recent studies have suggested that the microbiome may also influence the development of certain cancers such as colorectal cancer, and equally importantly, tumor response to systemic therapy, especially immunotherapy. Multiple groups are exploring the therapeutic utility of the microbiome to enhance clinical response through the use of defined oral therapeutics comprising living commensal bacteria, which would represent a new therapeutic modality. Exploiting the microbiome for therapeutic benefit is not without its challenges due to the heterogeneity of the gut microbiota across healthy donors and patients. In addition, many aspects of conventional small molecule and biologics drug discovery and development do not apply to this novel class of living drugs. We present an approach that leverages the concept of “reverse translation,” using genomic and immunologic characterization of patient samples from interventional studies to define and better understand the organisms and mechanisms that contribute to response or non-response to immunotherapy. We are investigating the relationship between the composition of the gut microbiome prior to therapy and the antitumor response in patients receiving checkpoint inhibitors (CPI), as well as how CPI treatment modulates the microbiome in both responders and nonresponders. Fecal and blood samples are collected before and during therapy from cancer patients who receive approved CPI; tumor types include renal, bladder, and NSCLC. Whole metagenomic shotgun sequencing of patient microbiomes is used to identify higher order (e.g., order- and family-level) “microbial signatures” that associate with response to CPI treatment. We then utilize proprietary algorithms that enable species- and strain-level resolution of microbial signatures. In addition, global and targeted metabolomics are used to identify functional pathways associated with outcome, and these pathways can be linked to species and strains identified by genomic analysis. Our discovery strategy iterates computational analyses and machine learning approaches with empirical in vitro and ex vivo screening of strains and consortia to inform selection and drive drug design. Data from such a comprehensive approach is invaluable for designing compositions of bacteria that form “functional ecological networks” that can impact response to CPI therapy. Finally, our microbial library of >14,000 isolates from healthy human subjects captures the phylogenetic diversity and functional breadth of the gastrointestinal microbiome, and provides a robust platform to build unique compositions. Such compositions, when tested in syngeneic tumor models in germ-free mice, can provide a preliminary readout of the contributions of members of the consortia and enable candidate identification. We present exam","PeriodicalId":309751,"journal":{"name":"Cancer and the Microbiome","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122884150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}