Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair(MMR). About 15% of sporadic colorectal cancers(CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting ...Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair(MMR). About 15% of sporadic colorectal cancers(CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting in mono-and di-nucleotide frameshifts to classify it as microsatellite instability-high(MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic nonMSI-H CRCs demonstrate frameshifts at di-and tetra-nucleotide microsatellites to classify it as MSIlow/elevated microsatellite alterations at selected tetranucleotide repeats(EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement. The trigger for MSH3 displacement appears to be inflammation and/or oxidative stress, and unlike MSI-H CRC patients, patients with MSI-L/EMAST CRCs show poor prognosis. These inflammatory-associated microsatellite alterations are a consequence of the local tumor microenvironment, and in theory, if the microenvironment is manipulated to lower inflammation, the microsatellite alterations and MSH3 dysfunction should be corrected. Here we describe the mechanisms and significance of inflammatory-associated microsatellite alterations, and propose three areas to deeply explore the consequences and prevention of inflammation's effect upon the DNA MMR system.展开更多
Background:With functionally heterogeneous cells,tumors comprise a complex ecosystem to promote tumor adaptability and evolution under strong selective pressure from the given microenvironment.Diversifying tumor cells...Background:With functionally heterogeneous cells,tumors comprise a complex ecosystem to promote tumor adaptability and evolution under strong selective pressure from the given microenvironment.Diversifying tumor cells or intra-tumor heterogeneity is essential for tumor growth,invasion,and immune evasion.However,no reliable method to classify tumor cell subtypes is yet available.In this study,we introduced the single-cell sequencing combined with copy number characteristics to identify the types of tumor cells in microsatellite stable(MSS)colorectal cancer(CRC).Methods:To characterize the somatic copy number alteration(SCNA)of MSS CRC in a single cell profile,we analyzed 26 tissue samples from 19 Korean patients(GSE132465,the Samsung Medical Center[SMC]dataset)and then verified our findings with 15 tissue samples from five Belgian patients(GSE144735,the Katholieke Universiteit Leuven 3[KUL3]dataset).The Cancer Genome Atlas(TCGA)cohort,GSE39582 cohort,and National Cancer Center(NCC)cohort(24 MSS CRC patients were enrolled in this study between March 2017 and October 2017)were used to validate the clinical features of prognostic signatures.Results:We employed single cell RNA-sequencing data to identify three types of tumor cells in MSS CRC by their SCNA characteristics.Among these three types of tumor cells,C1 and C3 had a higher SCNA burden;C1 had significant chromosome 13 and 20 amplification,whereas C3 was the polar opposite of C1,which exhibited deletion in chromosome 13 and 20.The three types of tumor cells exhibited various functions in the tumor microenvironment and harbored different mutations.C1 and C2 were linked to the immune response and hypoxia,respectively,while C3 was critical for cell adhesion activity and tumor angiogenesis.Additionally,one gene(OLFM4)was identified as epithelium-specific biomarker of better prognosis of CRC(TCGA cohort:P=0.0110;GSE39582 cohort:P=0.0098;NCC cohort:P=0.0360).Conclusions:On the basis of copy number characteristics,we illustrated tumor heterogeneity in MSS CRC and iden展开更多
Pancreatic cancer is one of the most aggressive cancers with a high mortality rate even among patients with early-stage disease.Although recent studies with novel therapeutic approaches have led to modest improvement ...Pancreatic cancer is one of the most aggressive cancers with a high mortality rate even among patients with early-stage disease.Although recent studies with novel therapeutic approaches have led to modest improvement in survival outcomes,limited progress is achieved for the use of immunotherapeutics in this challenging cancer.Immune checkpoint inhibitors,thus far,single-agent or in combination,have not yielded significant improvement in survival outcomes except in mismatch repair-deficient pancreatic cancer.The tumor microenvironment of pancreatic cancer has been considered as an attractive target for over a decade based on preclinical studies that suggested it may adversely affect drug delivery and antitumor immunity.In this review article,we elaborate on the biology of pancreatic cancer microenvironment,its highly complicated interaction with cancer cells,and the immune system.We also discuss plausible explanations that led to the failure of immune checkpoint inhibitors as therapeutic agents and the potential impacts of pancreatic cancer stroma on these negative studies.展开更多
Colorectal cancer(CRC)represents the second most common cancer in Europe with marked differences in prognosis and response to treatments.In the past years research showed emerging interest in genomic and immunologic f...Colorectal cancer(CRC)represents the second most common cancer in Europe with marked differences in prognosis and response to treatments.In the past years research showed emerging interest in genomic and immunologic fields.The clinical heterogeneity,that occurs during the pathogenesis of CRC,is driven by chromosomal alterations and defective function of DNA mismatch repair genes.CRC is classified in four consensus molecular subtypes(CMS)with different immunogenic characteristics and prognosis.CMS1 microsatellite instable(MSI)-like and CMS4,both characterized by high levels of immune infiltration,are recognized as the most immunogenic subtypes,even though functional characteristic leading to different prognosis are reported.In particular,MSI tumors have been identified as the best candidates for immunotherapy treatment and a number of studies have evaluated the efficacy of anti-programmed cell death ligand-1(PDL-1)and anti-cytotoxic T-lymphocyte-associated protein 4(CTLA4)in this setting.However,literature data show that the majority of patients with CRC have microsatellite stable(MSS)tumors and this status seems related to lower response to PDL-1/programmed cell death-1 or CTLA4 blockade.The aim of this paper is to investigate the role of immunotherapy in MSI and MSS CRC.展开更多
BACKGROUND The effectiveness of regorafenib plus programmed cell death-1(PD-1)inhibitor in treating microsatellite stable(MSS)metastatic colorectal cancer(mCRC)remains controversial.AIM To investigate the benefits of ...BACKGROUND The effectiveness of regorafenib plus programmed cell death-1(PD-1)inhibitor in treating microsatellite stable(MSS)metastatic colorectal cancer(mCRC)remains controversial.AIM To investigate the benefits of regorafenib combined with PD-1 inhibitor in treating MSS mCRC and explore indicators predicting response.METHODS This retrospective study included a total of 30 patients with microsatellite stable metastatic colorectal cancer treated with regorafenib combined with programmed cell death-1 inhibitor at Henan Provincial People’s Hospital between December 2018 and December 2020.During a 4-wk treatment cycle,regorafenib was performed for 3 continuous weeks.PD-1 inhibitor was intravenously injected starting on the first day of the oral intake of regorafenib.We reviewed tumor response,progression-free survival(PFS),overall survival,and treatment-related adverse events(TRAEs)and evaluated association between platelet-tolymphocyte ratio(PLR)and outcomes in this retrospective study.RESULTS Stable disease and progressive disease were found in 18(60.0%)and 12(40.0%)patients,respectively.The disease control rate was 60.0%.The median follow-up time was 12.0 mo,and median PFS was 3.4 mo[95%confidence interval(CI):2.2-4.6 mo].Of the 12 patients with progressive disease,10(83.3%)had liver metastasis before starting the combined treatment.Among the 18 patients with SD,10(55.6%)did not have liver metastases.One patient without liver metastases at baseline was found with a substantially prolonged PFS of 11.2 mo.The liver metastasis,the choice of programmed cell death-1 inhibitor other than nivolumab or pembrolizumab and previous exposure to regorafenib was’t associated with treatment outcome.The median PFS in the low-PLR group was 4.2 mo(95%CI:3.5-4.9 mo),compared with 2.8 mo(95%CI:1.4-4.2 mo)in the high-PLR group(P=0.005).The major TRAEs included hand-foot syndrome(33.3%),hypertension(23.3%),malaise(20.0%),and gastrointestinal reaction(16.7%).The incidence of grade 3 TRAEs was 13.3%(4/30),which comprised abnormal c展开更多
基金Supported by United States Public Health Service,Nos.DK067287,CA162147 and CA206010the A.Alfred Taubman Medical Research Institute of the University of Michigan
文摘Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair(MMR). About 15% of sporadic colorectal cancers(CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting in mono-and di-nucleotide frameshifts to classify it as microsatellite instability-high(MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic nonMSI-H CRCs demonstrate frameshifts at di-and tetra-nucleotide microsatellites to classify it as MSIlow/elevated microsatellite alterations at selected tetranucleotide repeats(EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement. The trigger for MSH3 displacement appears to be inflammation and/or oxidative stress, and unlike MSI-H CRC patients, patients with MSI-L/EMAST CRCs show poor prognosis. These inflammatory-associated microsatellite alterations are a consequence of the local tumor microenvironment, and in theory, if the microenvironment is manipulated to lower inflammation, the microsatellite alterations and MSH3 dysfunction should be corrected. Here we describe the mechanisms and significance of inflammatory-associated microsatellite alterations, and propose three areas to deeply explore the consequences and prevention of inflammation's effect upon the DNA MMR system.
文摘Background:With functionally heterogeneous cells,tumors comprise a complex ecosystem to promote tumor adaptability and evolution under strong selective pressure from the given microenvironment.Diversifying tumor cells or intra-tumor heterogeneity is essential for tumor growth,invasion,and immune evasion.However,no reliable method to classify tumor cell subtypes is yet available.In this study,we introduced the single-cell sequencing combined with copy number characteristics to identify the types of tumor cells in microsatellite stable(MSS)colorectal cancer(CRC).Methods:To characterize the somatic copy number alteration(SCNA)of MSS CRC in a single cell profile,we analyzed 26 tissue samples from 19 Korean patients(GSE132465,the Samsung Medical Center[SMC]dataset)and then verified our findings with 15 tissue samples from five Belgian patients(GSE144735,the Katholieke Universiteit Leuven 3[KUL3]dataset).The Cancer Genome Atlas(TCGA)cohort,GSE39582 cohort,and National Cancer Center(NCC)cohort(24 MSS CRC patients were enrolled in this study between March 2017 and October 2017)were used to validate the clinical features of prognostic signatures.Results:We employed single cell RNA-sequencing data to identify three types of tumor cells in MSS CRC by their SCNA characteristics.Among these three types of tumor cells,C1 and C3 had a higher SCNA burden;C1 had significant chromosome 13 and 20 amplification,whereas C3 was the polar opposite of C1,which exhibited deletion in chromosome 13 and 20.The three types of tumor cells exhibited various functions in the tumor microenvironment and harbored different mutations.C1 and C2 were linked to the immune response and hypoxia,respectively,while C3 was critical for cell adhesion activity and tumor angiogenesis.Additionally,one gene(OLFM4)was identified as epithelium-specific biomarker of better prognosis of CRC(TCGA cohort:P=0.0110;GSE39582 cohort:P=0.0098;NCC cohort:P=0.0360).Conclusions:On the basis of copy number characteristics,we illustrated tumor heterogeneity in MSS CRC and iden
文摘Pancreatic cancer is one of the most aggressive cancers with a high mortality rate even among patients with early-stage disease.Although recent studies with novel therapeutic approaches have led to modest improvement in survival outcomes,limited progress is achieved for the use of immunotherapeutics in this challenging cancer.Immune checkpoint inhibitors,thus far,single-agent or in combination,have not yielded significant improvement in survival outcomes except in mismatch repair-deficient pancreatic cancer.The tumor microenvironment of pancreatic cancer has been considered as an attractive target for over a decade based on preclinical studies that suggested it may adversely affect drug delivery and antitumor immunity.In this review article,we elaborate on the biology of pancreatic cancer microenvironment,its highly complicated interaction with cancer cells,and the immune system.We also discuss plausible explanations that led to the failure of immune checkpoint inhibitors as therapeutic agents and the potential impacts of pancreatic cancer stroma on these negative studies.
文摘Colorectal cancer(CRC)represents the second most common cancer in Europe with marked differences in prognosis and response to treatments.In the past years research showed emerging interest in genomic and immunologic fields.The clinical heterogeneity,that occurs during the pathogenesis of CRC,is driven by chromosomal alterations and defective function of DNA mismatch repair genes.CRC is classified in four consensus molecular subtypes(CMS)with different immunogenic characteristics and prognosis.CMS1 microsatellite instable(MSI)-like and CMS4,both characterized by high levels of immune infiltration,are recognized as the most immunogenic subtypes,even though functional characteristic leading to different prognosis are reported.In particular,MSI tumors have been identified as the best candidates for immunotherapy treatment and a number of studies have evaluated the efficacy of anti-programmed cell death ligand-1(PDL-1)and anti-cytotoxic T-lymphocyte-associated protein 4(CTLA4)in this setting.However,literature data show that the majority of patients with CRC have microsatellite stable(MSS)tumors and this status seems related to lower response to PDL-1/programmed cell death-1 or CTLA4 blockade.The aim of this paper is to investigate the role of immunotherapy in MSI and MSS CRC.
基金Supported by the Henan Provincial Department of Science and Technology,No. 212102310047
文摘BACKGROUND The effectiveness of regorafenib plus programmed cell death-1(PD-1)inhibitor in treating microsatellite stable(MSS)metastatic colorectal cancer(mCRC)remains controversial.AIM To investigate the benefits of regorafenib combined with PD-1 inhibitor in treating MSS mCRC and explore indicators predicting response.METHODS This retrospective study included a total of 30 patients with microsatellite stable metastatic colorectal cancer treated with regorafenib combined with programmed cell death-1 inhibitor at Henan Provincial People’s Hospital between December 2018 and December 2020.During a 4-wk treatment cycle,regorafenib was performed for 3 continuous weeks.PD-1 inhibitor was intravenously injected starting on the first day of the oral intake of regorafenib.We reviewed tumor response,progression-free survival(PFS),overall survival,and treatment-related adverse events(TRAEs)and evaluated association between platelet-tolymphocyte ratio(PLR)and outcomes in this retrospective study.RESULTS Stable disease and progressive disease were found in 18(60.0%)and 12(40.0%)patients,respectively.The disease control rate was 60.0%.The median follow-up time was 12.0 mo,and median PFS was 3.4 mo[95%confidence interval(CI):2.2-4.6 mo].Of the 12 patients with progressive disease,10(83.3%)had liver metastasis before starting the combined treatment.Among the 18 patients with SD,10(55.6%)did not have liver metastases.One patient without liver metastases at baseline was found with a substantially prolonged PFS of 11.2 mo.The liver metastasis,the choice of programmed cell death-1 inhibitor other than nivolumab or pembrolizumab and previous exposure to regorafenib was’t associated with treatment outcome.The median PFS in the low-PLR group was 4.2 mo(95%CI:3.5-4.9 mo),compared with 2.8 mo(95%CI:1.4-4.2 mo)in the high-PLR group(P=0.005).The major TRAEs included hand-foot syndrome(33.3%),hypertension(23.3%),malaise(20.0%),and gastrointestinal reaction(16.7%).The incidence of grade 3 TRAEs was 13.3%(4/30),which comprised abnormal c
