Objective: PTPRD and PTPRT are phosphatases of the JAK-STAT pathway related to immunotherapy.However, the role and mechanism of PTPRD and PTPRT mutations in multiple cancers remains unclear.Methods: Clinical data and ...Objective: PTPRD and PTPRT are phosphatases of the JAK-STAT pathway related to immunotherapy.However, the role and mechanism of PTPRD and PTPRT mutations in multiple cancers remains unclear.Methods: Clinical data and PTPRD/PTPRT mutation information from 12 cohorts were collected and classified as a discovery cohort and three validation cohorts. The association between PTPRD/PTPRT mutations and immunotherapeutic efficacy was analyzed. Then, the association between PTPRD/PTPRT mutation and immune profiles was analyzed using The Cancer Genome Atlas(TCGA) cohort.Results: A total of 2,392 patients across 20 cancer types were included in this study. Our results showed that patients harboring PTPRD/PTPRT mutation, especially co-mutations, had a significantly elevated response rate to immunotherapy in multiple cancers. Patients with PTPRD/PTPRT mutation had a higher objective response rate(ORR)(P=0.002), longer overall survival(OS)(P=0.005) and progression-free survival(PFS)(P=0.038).Importantly, the above findings were further verified in validation cohorts. In addition, we found that the PTPRD/PTPRT co-mutations(co-mut) subgroup exhibited an immune-activated phenotype, the wild-type subgroup tended to have an immune-desert phenotype, and the uni-mutation(uni-mut) subgroup might have an immune-mixed phenotype. Our further analyses suggested that combining programmed cell death ligand 1(PDL1) expression and PTPRD/PTPRT mutation can be used to screen patients who may benefit from immunotherapy.Conclusions: PTPRD/PTPRT mutation could serve as a potential predictive biomarker for cancer immunotherapy.展开更多
Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic...Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection.However,the PTPRD-expressing hepatic cell types,signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans,and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis(MASH).Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays.The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice,showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function.Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease.We further validated PTPRD as a STAT3 phosphatase in the liver,acting as a regulator of peroxisomal fatty acid metabolism.During MASH,low PTPRD led to increased liver steatosis in Ptprd+/−mice and a pronounced unfolded protein response,which impacts insulin signalling.Accordingly,silencing of PTPRD blunted insulin-induced AKT phosphorylation.Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis,which is recapitulated in clinical manifestations of metabolic liver disease.展开更多
基金supported by grants from the joint fund for key projects of National Natural Science Foundation of China (No. U20A20371)Beijing Municipal Administration of Hospitals Incubating Program (No. PX2019040 and No. PX2019039)Beijing Municipal Natural Science Foundation (No. 7222023)。
文摘Objective: PTPRD and PTPRT are phosphatases of the JAK-STAT pathway related to immunotherapy.However, the role and mechanism of PTPRD and PTPRT mutations in multiple cancers remains unclear.Methods: Clinical data and PTPRD/PTPRT mutation information from 12 cohorts were collected and classified as a discovery cohort and three validation cohorts. The association between PTPRD/PTPRT mutations and immunotherapeutic efficacy was analyzed. Then, the association between PTPRD/PTPRT mutation and immune profiles was analyzed using The Cancer Genome Atlas(TCGA) cohort.Results: A total of 2,392 patients across 20 cancer types were included in this study. Our results showed that patients harboring PTPRD/PTPRT mutation, especially co-mutations, had a significantly elevated response rate to immunotherapy in multiple cancers. Patients with PTPRD/PTPRT mutation had a higher objective response rate(ORR)(P=0.002), longer overall survival(OS)(P=0.005) and progression-free survival(PFS)(P=0.038).Importantly, the above findings were further verified in validation cohorts. In addition, we found that the PTPRD/PTPRT co-mutations(co-mut) subgroup exhibited an immune-activated phenotype, the wild-type subgroup tended to have an immune-desert phenotype, and the uni-mutation(uni-mut) subgroup might have an immune-mixed phenotype. Our further analyses suggested that combining programmed cell death ligand 1(PDL1) expression and PTPRD/PTPRT mutation can be used to screen patients who may benefit from immunotherapy.Conclusions: PTPRD/PTPRT mutation could serve as a potential predictive biomarker for cancer immunotherapy.
基金supported by the European Union(ERC-AdG-2014 HEPCIR ERC POC PRELICAN 755460,ERC POC HEPCAN 862551 to TFB,EU H2020 HEPCAR 667273 to TFB and JL,HORIZON-HLTH-2021-DISEASE-04-07 D-SOLVE#101057917 to TFB and JL,IP-cure-B project#847939 to FZ,ERC-AdG-2020-101021417 to YH)the French Cancer Agency(TheraHCC2.0 IHU201901299 to TFB)+9 种基金the Agence Nationale de la Recherche(ANR-21-RHUS-001 to TFB)the ANRS Maladies infectieusesémergentes(ANRS-MIE)(ECTZ103701,ECTZ131760,ECTZ160436,ECTZ171594 to JL,ECTZ104017 and ECTZ75178 to TFB,ECTZ4446 and ECTZ206376 to AARS)the Fondation de l’Universitéde Strasbourg(HEPKIN)(TBA-DON-0002),SATT Conectus,University of Strasbourg(CANCLAU)(TFB)the Inserm Plan Cancer 2019-2023the US National Institutes of Health(CA233794,CA255621,CA282178,CA288375 and CA283935 to YH)the Cancer Prevention and Research Institute of Texas(RR180016,RP200554 to YH)The AEPIC animal facility platform is financially supported by the CoRTecS network of the University of StrasbourgThis work of the Interdisciplinary Thematic Institute IMCBio,as part of the ITI 2021-2028 programme of the University of Strasbourg,CNRS and Inserm,was supported by IdEx Unistra(ANR-10-IDEX-0002)SFRI-STRAT’US project(ANR 20-SFRI-0012)EUR IMCBio(ANR-17-EURE-0023)under the framework of the French Investments for the Future Programme,as well as state funds managed within the France 2030 programme(reference ANR-21-RHUS-0001).
文摘Objective Impaired hepatic expression of protein tyrosine phosphatase delta(PTPRD)is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection.However,the PTPRD-expressing hepatic cell types,signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans,and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis(MASH).Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays.The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice,showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function.Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease.We further validated PTPRD as a STAT3 phosphatase in the liver,acting as a regulator of peroxisomal fatty acid metabolism.During MASH,low PTPRD led to increased liver steatosis in Ptprd+/−mice and a pronounced unfolded protein response,which impacts insulin signalling.Accordingly,silencing of PTPRD blunted insulin-induced AKT phosphorylation.Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis,which is recapitulated in clinical manifestations of metabolic liver disease.
