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
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
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
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.
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.
