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• W4312158520 abstract "Metformin treatment rescues CD8+ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLDJournal of HepatologyVol. 77Issue 3PreviewNon-alcoholic steatohepatitis (NASH) represents the fastest growing underlying cause of hepatocellular carcinoma (HCC) and has been shown to impact immune effector cell function. The standard of care for the treatment of advanced HCC is immune checkpoint inhibitor (ICI) therapy, yet NASH may negatively affect the efficacy of ICI therapy in HCC. The immunologic mechanisms underlying the impact of NASH on ICI therapy remain unclear. Full-Text PDF We read with interest the study by Wabitsch et al., which showed that metformin could rescue the CD8+ T-cell response to immune checkpoint inhibitor (ICI) therapy in mice with non-alcoholic steatohepatitis (NASH)-associated liver cancer.[1]Wabitsch S. McCallen J.D. Kamenyeva O. Ruf B. McVey J.C. Kabat J. et al.Metformin treatment rescues CD8(+) T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD.J Hepatol. 2022; 77: 748-760Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar As the first-line treatment for type 2 diabetes, metformin is known for its glucose-lowering actions. Accumulating evidence also suggests that metformin may inhibit tumourigenesis by reducing insulin levels and inducing energetic stress.[2]Pernicova I. Korbonits M. Metformin--mode of action and clinical implications for diabetes and cancer.Nat Rev Endocrinol. 2014; 10: 143-156Crossref PubMed Scopus (832) Google Scholar The authors demonstrated that metformin improved the motility and metabolic functions of hepatic CD8+ T cells in NASH mice with liver cancer receiving anti-PD1 treatment.[1]Wabitsch S. McCallen J.D. Kamenyeva O. Ruf B. McVey J.C. Kabat J. et al.Metformin treatment rescues CD8(+) T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD.J Hepatol. 2022; 77: 748-760Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Taken together with the recently reported association between non-viral aetiologies of hepatocellular carcinoma (HCC) and reduced immunotherapy efficacy,[3]Pfister D. Núñez N.G. Pinyol R. Govaere O. Pinter M. Szydlowska M. et al.NASH limits anti-tumour surveillance in immunotherapy-treated HCC.Nature. 2021; 592: 450-456Crossref PubMed Scopus (373) Google Scholar this work suggests a potential use of metformin as an adjunct to ICI therapy to treat patients with NASH-associated HCC. Whether metformin improves CD8+ responses and the anti-tumour effect of immunotherapy in HCC regardless of aetiology has not been investigated. Therefore, we evaluated the therapeutic effects of metformin on patients with advanced HCC undergoing immunotherapy in a multi-centre cohort from Hong Kong and Australia. We included 397 patients with advanced HCC who had received at least one dose of immunotherapy (nivolumab, pembrolizumab, ipilimumab and others). Of these, 139 (35.0%) patients had diabetes, of whom 80 (57.6%) received metformin. The dominant HCC aetiology was chronic viral hepatitis (n = 293, 72.7%), followed by NASH (n = 39, 9.8%). The primary outcome was overall survival (OS), analysed using Cox models. There was no difference in survival among patients with diabetes (hazard ratio [HR] 1.06; 95% CI 0.84-1.34; p = 0.599), viral vs. non-viral aetiology (HR 1.05; 95% CI 0.78-1.41; p = 0.761), and metformin users (HR 0.97; 95% CI 0.73-1.29; p = 0.841) in univariable analysis (Table 1). In patients with diabetes, metformin also did not impact OS (HR 0.84; 95% CI 0.58-1.23; p = 0.376). After adjusting for age, sex, liver disease aetiology, albumin-bilirubin [ALBI]-grade, alpha-foetoprotein [AFP], platelets, and alanine aminotransferase, the HRs for metformin remained non-significant in all patients (HR 1.02; 95% CI 0.76-1.37; p = 0.908) and patients with diabetes (HR 0.82; 95% CI 0.55-1.21; p = 0.314). The HRs for diabetes and viral vs. non-viral aetiology remained insignificant in multivariable analyses.Table 1Univariate and multivariable analyses by Cox proportional hazards model on the impact of metformin use, presence of disbates, and viral vs. non-viral aetiology on overall survival in all patients, and metformin use on overall survival in diabetes subgroup.CohortsNo. of patientsUnivariate analysisMultivariable model 1Multivariable model 2HR (95% CI)p valueAdjusted HR (95% CI)p valueAdjusted HR (95% CI)p valueMetformin use in all patients800.97 (0.73-1.29)0.8411.05 (0.78-1.41)0.7731.02 (0.76-1.37)0.908Metformin use in diabetes subgroup800.84 (0.58-1.23)0.3760.85 (0.58-1.26)0.4250.82 (0.55-1.21)0.314Presence of diabetes in all patients1391.06 (0.84-1.34)0.5991.11 (0.86-1.44)0.4161.09 (0.84-1.43)0.493Viral vs. non-viral aetiology in all patients293/1041.05 (0.78-1.41)0.7611.01 (0.74-1.36)0.9650.96 (0.71-1.29)0.782Multivariable model 1: adjusted for age, sex, HCC aetiology.Multivariable model 2: adjusted for age, sex, HCC aetiology, ALBI-grade, alpha-foetoprotein, platelets, alanine aminotransferase.ALBI, albumin-bilirubin; HR, hazard ratio. Open table in a new tab Multivariable model 1: adjusted for age, sex, HCC aetiology. Multivariable model 2: adjusted for age, sex, HCC aetiology, ALBI-grade, alpha-foetoprotein, platelets, alanine aminotransferase. ALBI, albumin-bilirubin; HR, hazard ratio. In our clinical validation, HR for OS is non-significantly lower in diabetic patients co-treated with metformin and ICI compared with ICI monotherapy. Compared to the whole cohort, metformin provides no survival benefits. The non-significant results in the diabetes subgroup could be explained by the dominant viral aetiology of our cohort. The impaired efficacy of immunotherapy in NASH-HCC compared to viral-HCC lies in a difference in tumour microenvironment. Immune surveillance in NASH-HCC is impaired, with exhausted and aberrantly activated CD8+PD1+ T cells, which are expanded by immunotherapy, promoting tumourigenesis.[3]Pfister D. Núñez N.G. Pinyol R. Govaere O. Pinter M. Szydlowska M. et al.NASH limits anti-tumour surveillance in immunotherapy-treated HCC.Nature. 2021; 592: 450-456Crossref PubMed Scopus (373) Google Scholar With the distinct carcinogenic pathways between NASH and viral aetiologies[4]Chan L.L. Chan S.L. Novel perspectives in immune checkpoint inhibitors and the management of non-alcoholic steatohepatitis-related hepatocellular carcinoma.Cancers. 2022; 14Crossref Scopus (4) Google Scholar,[5]Ghouri Y.A. Mian I. Rowe J.H. Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis.J Carcinog. 2017; 16: 1Crossref PubMed Scopus (531) Google Scholar and the proven survival advantage associated with viral-HCC in patients on ICIs,[3]Pfister D. Núñez N.G. Pinyol R. Govaere O. Pinter M. Szydlowska M. et al.NASH limits anti-tumour surveillance in immunotherapy-treated HCC.Nature. 2021; 592: 450-456Crossref PubMed Scopus (373) Google Scholar metformin’s therapeutic effects (if any) on modifying the immune microenvironment and prolonging survival may be masked in our cohort. Despite robust evidence on metformin reducing HCC risk in the diabetic population,[4]Chan L.L. Chan S.L. Novel perspectives in immune checkpoint inhibitors and the management of non-alcoholic steatohepatitis-related hepatocellular carcinoma.Cancers. 2022; 14Crossref Scopus (4) Google Scholar the effect of metformin on HCC survival remains controversial. Although metformin use is associated with prolonged survival among patients with HCC after curative therapies such as resection, liver transplant and radiofrequency ablation, its effect on advanced HCC remains unclear.[6]Zhou J. Ke Y. Lei X. Wu T. Li Y. Bao T. et al.Meta-analysis: the efficacy of metformin and other anti-hyperglycemic agents in prolonging the survival of hepatocellular carcinoma patients with type 2 diabetes.Ann Hepatol. 2020; 19: 320-328Crossref PubMed Scopus (25) Google Scholar,[7]Schulte L. Scheiner B. Voigtländer T. Koch S. Schweitzer N. Marhenke S. et al.Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma.Liver Int. 2019; 39: 714-726Crossref PubMed Scopus (40) Google Scholar In patients with diabetes and advanced HCC, those treated with sorafenib and metformin had a survival disadvantage compared with those receiving sorafenib only, as metformin conferred resistance to sorafenib via upregulation of SIRT-3.[8]Casadei Gardini A. Faloppi L. De Matteis S. Foschi F.G. Silvestris N. Tovoli F. et al.Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: validation study and biological rationale.Eur J Cancer. 2017; 86: 106-114Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar After the IMBrave150 trials, atezolizumab and bevacizumab have become the new standard treatment of advanced HCC, and there is great excitement surrounding combinations of different ICIs and tyrosine kinase inhibitors.[4]Chan L.L. Chan S.L. Novel perspectives in immune checkpoint inhibitors and the management of non-alcoholic steatohepatitis-related hepatocellular carcinoma.Cancers. 2022; 14Crossref Scopus (4) Google Scholar Further studies should be conducted to elucidate whether metformin induces resistance to these combination therapies, as it does to sorafenib. In our cohort, the benefits of metformin (if any) could also be limited by poorer baseline liver function and prior lines of locoregional and/or systemic treatments before ICI therapy (cf. first line ICI therapy in Wabitsch et al. murine studies). Our validation has several limitations inherent to its observational nature. Our cohorts were retrospective with limited sample size, so a subgroup analysis in patients with NASH could not be performed. Additionally, the effects of metformin may become insignificant due to confounding. Cancer staging data were unavailable, hence ALBI grading and serum AFP, which may reflect disease severity, were used as covariates in the multivariable analysis. Moreover, the dosage and the concomitant or sequential use of metformin were not well controlled. We lack data on cancer progression or ICI treatment response. Therefore, we could not analyse progression-free survival or response rate, which might better reflect ICI efficacy. In conclusion, we congratulate Wabitsch et al. for their well-designed study. In our clinical validation, metformin use was not associated with improved survival in patients with HCC receiving immunotherapy, regardless of diabetes status. The findings should be further validated in prospective studies with larger sample sizes. The authors received no financial support to produce this manuscript. Terry Yip has served as an advisory committee member and a speaker for Gilead Sciences. The other authors declare that they have no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details. Terry Yip and Ken Liu have full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Huapeng Lin, Dorothy Yiu, Ken Liu and Terry Yip were responsible for the study concept and design. Huapeng Lin, Dorothy Yiu and Simone Chin were responsible for the acquisition of data. Huapeng Lin and Dorothy Yiu were responsible for data analysis. Huapeng Lin, Dorothy Yiu Ken Liu and Terry Yip drafted the manuscript. All authors had significant contribution to the intellectual content of the manuscript and approved its final version. The data that support the findings of this study are available from Hospital Authority. Restrictions apply to the availability of these data, which were used under license for this study. The following are the supplementary data to this article: Download .pdf (.28 MB) Help with pdf files Multimedia component 1" @default.
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