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Jason Behary, Lan Gong, Nadia Amorim, Anita Raposo ,

Effect of the microbiota on the peripheral immune response in patients with NAFLD-associated hepatocellular carcinoma. Jason Behary, Lan Gong, Nadia Amorim, Anita Raposo , Xiao-Tao Jiang, Huimin Zheng, Emad El-Omar, Amany Zekry. Microbiome Research Centre, UNSW Sydney

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Jason Behary, Lan Gong, Nadia Amorim, Anita Raposo ,

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  1. Effect of the microbiota on the peripheral immune response in patients with NAFLD-associated hepatocellular carcinoma Jason Behary, Lan Gong, Nadia Amorim, Anita Raposo, Xiao-Tao Jiang, Huimin Zheng, Emad El-Omar, AmanyZekry Microbiome Research Centre, UNSW Sydney Department of Gastroenterology, St George Hospital, Sydney Australia

  2. Disclosure • None to declare

  3. Alteration of the peripheral and intrahepatic immune response is well described in NAFLD related HCC1 • Upregulation of regulatory T-cells (Treg) in peripheral blood and HCC tissue have been shown to promote HCC progression and are associated with poor outcomes1,2 • The microbiome is emerging as a key factor in the pathogenesis of NAFLD-HCC, interacting with the liver via the gut-liver axis3 Sachdeva M et al, WJH 2015 Tu JF et al, Nature 2016 Ponzianiet al, Hepatology 2019

  4. Aims To confirm that gut dysbiosis occurs in NAFLD related HCC To determine whether this dysbiosis in NAFLD related HCC can influence the host peripheral immune response

  5. Patient recruitment • Cohorts: • Patients undergoing surgical resection for HCC (NAFLD & non-NAFLD) • NAFLD cirrhosis (Child Pugh A) • Healthy controls • Exclusion criteria: • Portal hypertension • Antibiotic administration in the last 3 months • + other exclusion criteria..

  6. Methods Microbiome analysis 16s rRNA sequencing Control fecal extract “cell lysate” (n=5) NAFLD HCC fecal extract “cell lysate” (n=5) Heat treated, sonicated, no LPS Ex-vivo culture model PBMCs Control PBMCs (n=5) NAFLD HCC PBMCs (n=5) 360 samples Host immune response measured by flow cytometry 2. Cytokines measured in cell culture media with magnetic bead-based immunoassay Adapted from Cekanaviciutet al, PNAS, 2017

  7. Results

  8. Patient cohort (at time of experiment) Values expressed as means ( SD) * p < 0.05 by one-way ANOVA, post hoc Tukey’s test compared to control group

  9. NAFLD and NAFLD-HCC are characterized by dysbiosis Relative abundance (phylum) Fold change in composition ⍺-diversity * * * p< 0.05, one-way ANOVA; Holm-Sidak multiple comparison test, compared to control group

  10. PBMCsincubationwith cancer fecalextractinduces host regulatoryT-cells (Treg) + Control fecal extract + Cancer fecal extract 7.69% 7.69% 30.8% FoxP3 CD25 *p <0.05 by t-test * p <0.05 by t-test

  11. PBMCs incubation with cancer fecal extract dampens host antigen presenting (HLADR+) and B cells (CD20+) + Control fecal extract + Cancer fecal extract 10.2% 2.87% ** p<0.01, by t-test HLADR+ CD20+ ** p<0.01, by t-test

  12. PBMCs incubation with cancer fecalextractdampens host T-helper (CD4+) and CD8+ T-cells + Control fecal extract + Cancer fecal extract 13.2% 4.02% 2.43% 0.2% CD8+ CD4+ ** p<0.01, by t-test

  13. PBMCs incubation with cancer fecal extract promotes host natural killer (NK) and natural killer T-cells (NKT) + Control fecal extract + Cancer fecal extract 6.25% 73.5% * p <0.05 by t-test CD56+ IFN- * p <0.05 by t-test

  14. Fecal extract induced alteration in secreted cytokines and chemokines in control PBMC culture media

  15. Cancer fecal extract effect on peripheral immune response

  16. Cancer fecal extract effect on peripheral immune response

  17. Conclusion • NAFLD-HCC is characterized by dysbiosis • Dysbiosis in NAFLD-HCC results in a peripheral immunotolerant phenotype • Ongoing work, 150+ patients recruited, national collaboration • Potential clinical implications • Identification of patients at risk of HCC progression and response to therapy

  18. Acknowledgements • Glenn Family Foundation • St George Hospital Liver Clinic Research Staff • St George and Sutherland Clinical School, UNSW Sydney • St George and Sutherland Research Foundation (SSMRF) • Collaborators: • RoyalPrinceAlfredHospital • Prof Geoff McCaughan • Dr Avik Majumdar • Nepean hospital • St Vincent's Hospital • John Hunter hospital • Centenary Institute, USYD • Prof Mark Gorrell • Ramaciotti Centre for Genomics, UNSW Sydney • Patients • A/Prof Amany Zekry • Prof Emad El-Omar • Microbiome Research Centre • Dr Lan Gong • Dr Nadia Amorim • Dr Anita Raposo • Dr Xiao-Tao Jiang • Dr Huimin Zheng • University Postgraduate Award, UNSW Sydney • Translational Cancer Research Network (TCRN) PhD Award, Cancer Institute NSW • Terry Bolin PhD Award, The Gut Foundation, GESA

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