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Single-cell profiling of the copy-number heterogeneity in colorectal cancer

Chinese Medical Journal 2023年第6期136卷 707-718页

作者： Shiyu Song Lin Feng Kexing Xi Zhigang Sun Deyang Kong Zhenkai Luo Wei Pei Haizeng Zhang Department of Colorectal Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Lab of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Molecular Oncology Department of Etiology and CarcinogenesisNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

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

关键词： Somatic copy number alteration microsatellite stable Colorectal cancer Single cell RNA-sequencing Intra-tumor genetic heterogeneity

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Regorafenib combined with programmed cell death-1 inhibitor against refractory colorectal cancer and the platelet-to-lymphocyte ratio’s prediction on effectiveness

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World Journal of Gastrointestinal Oncology 2022年第4期14卷 920-934页

作者： Yu-Jie Xu Peng Zhang Jin-Long Hu Hong Liang Yan-Yan Zhu Yao Cui Po Niu Min Xu Ming-Yue Liu Department of Oncology Henan Provincial People's HospitalPeople's Hospital of Zhengzhou UniversityZhengzhou 450003Henan ProvinceChina Department of Gastrointestinal Surgery Henan Provincial People's HospitalPeople's Hospital of Zhengzhou UniversityZhengzhou 450003Henan ProvinceChina Department of Hepatology The Third People's Hospital of ZhengzhouZhengzhou 450003Henan ProvinceChina

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 capil

关键词： Colorectal neoplasms microsatellite stable Programmed cell death-1 inhibitor Platelet-tolymphocyte ratio Regorafenib Progression-free survival

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The tumor microenvironment of pancreatic adenocarcinoma and immune checkpoint inhibitor resistance: a perplex relationship

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Cancer Drug Resistance 2020年第4期3卷 699-709页

作者： Irem Sahin Sevda Turen Pranav Santapuram Ibrahim Halil Sahin Baskent University School of Medicine Department of Medicine AnkaraAnkara 06810Turkey TC Istanbul Kültür University Faculty of Health SciencesDepartment of NursingIstanbul 34158Turkey Emory University School of Medicine Department of MedicineAtlantaGA 30322USA Moffitt Cancer Center Department of Gastrointestinal OncologyTampaFL 33612USA

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.

关键词： Pancreatic adenocarcinoma durvalumab nivolumab ipilimumab pembrolizumab immune checkpoint inhibitors immunotherapy resistance mismatch repair deficient microsatellite instability high microsatellite stable tumor-associated macrophages myeloid-derived suppressor cells T regs T cells

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