Background:Numerous long RNAs were detected in extracellular vesicles(EVs),some of which were related with the tissue origins and immune cell types.This study examined the molecular basis of different traditional Chin...Background:Numerous long RNAs were detected in extracellular vesicles(EVs),some of which were related with the tissue origins and immune cell types.This study examined the molecular basis of different traditional Chinese medicine syndrome diagnoses(also called syndrome differentiation)in pancreatic ductal adenocarcinoma.Methods:128 pancreatic ductal adenocarcinoma patients with different syndrome diagnoses were retrospectively reviewed in this study.Long RNA sequencing was conducted to analyze the EV long RNA profile of plasma samples.Differentially regulated EV long RNAs were annotated and assessed for Gene Ontology pathway enrichment using DAVID.The online program xCell were used to perform the cell-type enrichment analysis.Results:An average of 15,000 annotated genes,mainly including messenger RNAs,were stably detected per sample.Different syndrome diagnoses exhibited unique EV mRNA expression profiles and therefore different enriched pathways.Gene Set Enrichment Analysis discovered transforming growth factor-βand kirsten rat sarcoma viral oncogene homolog signaling activation as the hallmarks of cancer with Shi-Re syndrome.Cell-type enrichment analysis also revealed a varied inflammation/immune cell type distribution among patients with or without Shi-Re diagnosis.Mast cells,platelets and Tregs were significantly enriched but basophils,common lymphoid progenitors,dendritic cells,and conventional dendritic cells were decreased in patients with Shi-Re diagnosis compared with patients without Shi-Re diagnosis.Conclusion:We identified the hallmarks of cancer with different syndrome diagnoses based on plasma EV long RNA sequencing.In particular,transforming growth factor-βand kirsten rat sarcoma viral oncogene homolog signaling activation were the hallmarks of Shi-Re syndrome,which contribute to shape an inflammatory/immune-suppressive tumor microenvironment in pancreatic ductal adenocarcinoma.展开更多
Background Immune checkpoint inhibitors(ICIs)shed new light on triple-negative breast cancer(TNBC),but only a minority of patients demonstrate response.Therefore,adaptive immune resistance(AIR)needs to be further defi...Background Immune checkpoint inhibitors(ICIs)shed new light on triple-negative breast cancer(TNBC),but only a minority of patients demonstrate response.Therefore,adaptive immune resistance(AIR)needs to be further defined to guide the development of ICI regimens.Methods Databases,including The Cancer Genome Atlas,Gene Ontology Resource,University of California Santa Cruz Genome Browser,and Pubmed,were used to screen epigenetic modulators,regulators for CD8+T cells,and transcriptional regulators of programmed cell death-ligand 1(PD-L1).Human peripheral blood mononuclear cell(Hu-PBMC)reconstruction mice were adopted for xenograft transplantation.Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed.RNA-sequencing,Western blotting,qPCR and immunohistochemistry were used to assess gene expression.Coculture assays were performed to evaluate the regulation of TNBC cells on T cells.Chromatin immunoprecipitation and transposase-accessible chromatin sequencing were used to determine chromatin-binding and accessibility.Results The epigenetic modulator AT-rich interaction domain 1A(ARID1A)gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients.Low ARID1A expression in TNBC,causing an immunosuppressive microenvironment,promoted AIR and inhibited CD8+T cell infiltration and activity through upregulating PD-L1.However,ARID1A did not directly regulate PD-L1 expression.We found that ARID1A directly bound the promoter of nucleophosmin 1(NPM1)and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression,further activating PD-L1 transcription.In Hu-PBMC mice,atezolizumab demonstrated the potential to reverse ARID1A deficiency-induced AIR in TNBC by reducing tumor malignancy and activating anti-tumor immunity.In CTR20191353,ARID1A-low patients derived more benefit from pucotenlimab compared to ARID1A-high patients.Conclusions In AIR epigenetics,low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD-L1 axis,leading to poor outcome but sensitivity to ICI treatment.展开更多
基金supported by the National Natural Science Foundation of China(82230122,82025035,82104612)Shanghai Municipal Health Commission program(ZY(2021-2023)-0205-02)the Science Foundation for Young Scholars of Zhongshan Hospital,Fudan University(grant No.2021ZSQN70).
文摘Background:Numerous long RNAs were detected in extracellular vesicles(EVs),some of which were related with the tissue origins and immune cell types.This study examined the molecular basis of different traditional Chinese medicine syndrome diagnoses(also called syndrome differentiation)in pancreatic ductal adenocarcinoma.Methods:128 pancreatic ductal adenocarcinoma patients with different syndrome diagnoses were retrospectively reviewed in this study.Long RNA sequencing was conducted to analyze the EV long RNA profile of plasma samples.Differentially regulated EV long RNAs were annotated and assessed for Gene Ontology pathway enrichment using DAVID.The online program xCell were used to perform the cell-type enrichment analysis.Results:An average of 15,000 annotated genes,mainly including messenger RNAs,were stably detected per sample.Different syndrome diagnoses exhibited unique EV mRNA expression profiles and therefore different enriched pathways.Gene Set Enrichment Analysis discovered transforming growth factor-βand kirsten rat sarcoma viral oncogene homolog signaling activation as the hallmarks of cancer with Shi-Re syndrome.Cell-type enrichment analysis also revealed a varied inflammation/immune cell type distribution among patients with or without Shi-Re diagnosis.Mast cells,platelets and Tregs were significantly enriched but basophils,common lymphoid progenitors,dendritic cells,and conventional dendritic cells were decreased in patients with Shi-Re diagnosis compared with patients without Shi-Re diagnosis.Conclusion:We identified the hallmarks of cancer with different syndrome diagnoses based on plasma EV long RNA sequencing.In particular,transforming growth factor-βand kirsten rat sarcoma viral oncogene homolog signaling activation were the hallmarks of Shi-Re syndrome,which contribute to shape an inflammatory/immune-suppressive tumor microenvironment in pancreatic ductal adenocarcinoma.
基金National Science and Technology Major Project.Grant Number:2020ZX09201-013。
文摘Background Immune checkpoint inhibitors(ICIs)shed new light on triple-negative breast cancer(TNBC),but only a minority of patients demonstrate response.Therefore,adaptive immune resistance(AIR)needs to be further defined to guide the development of ICI regimens.Methods Databases,including The Cancer Genome Atlas,Gene Ontology Resource,University of California Santa Cruz Genome Browser,and Pubmed,were used to screen epigenetic modulators,regulators for CD8+T cells,and transcriptional regulators of programmed cell death-ligand 1(PD-L1).Human peripheral blood mononuclear cell(Hu-PBMC)reconstruction mice were adopted for xenograft transplantation.Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed.RNA-sequencing,Western blotting,qPCR and immunohistochemistry were used to assess gene expression.Coculture assays were performed to evaluate the regulation of TNBC cells on T cells.Chromatin immunoprecipitation and transposase-accessible chromatin sequencing were used to determine chromatin-binding and accessibility.Results The epigenetic modulator AT-rich interaction domain 1A(ARID1A)gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients.Low ARID1A expression in TNBC,causing an immunosuppressive microenvironment,promoted AIR and inhibited CD8+T cell infiltration and activity through upregulating PD-L1.However,ARID1A did not directly regulate PD-L1 expression.We found that ARID1A directly bound the promoter of nucleophosmin 1(NPM1)and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression,further activating PD-L1 transcription.In Hu-PBMC mice,atezolizumab demonstrated the potential to reverse ARID1A deficiency-induced AIR in TNBC by reducing tumor malignancy and activating anti-tumor immunity.In CTR20191353,ARID1A-low patients derived more benefit from pucotenlimab compared to ARID1A-high patients.Conclusions In AIR epigenetics,low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD-L1 axis,leading to poor outcome but sensitivity to ICI treatment.
