Neoantigen vaccines are one of the most effective immunotherapies for personalized tumour treatment.The current immunogen design of neoantigen vaccines is usually based on whole-genome sequencing(WGS)and bioinformatic...Neoantigen vaccines are one of the most effective immunotherapies for personalized tumour treatment.The current immunogen design of neoantigen vaccines is usually based on whole-genome sequencing(WGS)and bioinformatics prediction that focuses on the prediction of binding affinity between peptide and MHC molecules,ignoring other peptide-presenting related steps.This may result in a gap between high prediction accuracy and relatively low clinical effectiveness.In this study,we designed an integrated in-silico pipeline,Neo-intline,which started from the SNPs and indels of the tumour samples to simulate the presentation process of peptides in-vivo through an integrated calculation model.Validation on the benchmark dataset of TESLA and clinically validated neoantigens illustrated that neo-intline could outperform current state-of-the-art tools on both sample level and melanoma level.Furthermore,by taking the mouse melanoma model as an example,we verified the effectiveness of 20 neoantigens,including 10 MHC-I and 10 MHC-II peptides.The in-vitro and in-vivo experiments showed that both peptides predicted by Neo-intline could recruit corresponding CD4^(+)T cells and CD8^(+)T cells to induce a T-cell-mediated cellular immune response.Moreover,although the therapeutic effect of neoantigen vaccines alone is not sufficient,combinations with other specific therapies,such as broad-spectrum immune-enhanced adjuvants of granulocyte-macrophage colony-stimulating factor(GM-CSF)and polyinosinic-polycytidylic acid(poly(I:C)),or immune checkpoint inhibitors,such as PD-1/PD-L1 antibodies,can illustrate significant anticancer effects on melanoma.Neo-intline can be used as a benchmark process for the design and screening of immunogenic targets for neoantigen vaccines.展开更多
Recently,a new type of unknown virus causing severe acute res-piratory infection was reported in Wuhan city,Hubei province,China(WHO,2020b).Infection of this virus was first reported in December 2019,and origin of the...Recently,a new type of unknown virus causing severe acute res-piratory infection was reported in Wuhan city,Hubei province,China(WHO,2020b).Infection of this virus was first reported in December 2019,and origin of the virus was traced back to a large seafood/wide animal market in Wuhan city.The serious clinical symptoms of the viral infection,including fever,dry cough,dys-pnea,and pneumonia,may result in progressive respiratory failure and even death.Moreover,the quick spread of the virus has caused an epidemic in China,as well as infection cases worldwide.The whole-genome sequence of Wuhan new virus(WH-Human_.1)was first released on January 10,2020(Zhang,2020),followed by additional ones released in Global Initiative on Sharing All Influ-enza Data(GISAID)(Shu and McCauley,2017).Later,this new virus was determined and announced as a new type of coronavirus(CoV;2019-nCoV)by the World Health Organization(WHO,2020a).展开更多
基金We wish to thank all members of our laboratory for their helpful suggestions and support.This study was supported by grants from the National Natural Science Foundation of China(32370697,31900483)the Shanghai Sailing Program(19YF1441100)+1 种基金the Shanghai Science&Technology Basic Research Program(18JC1414400)the Key Science and Technology Program of Henan Province(212102310872).
文摘Neoantigen vaccines are one of the most effective immunotherapies for personalized tumour treatment.The current immunogen design of neoantigen vaccines is usually based on whole-genome sequencing(WGS)and bioinformatics prediction that focuses on the prediction of binding affinity between peptide and MHC molecules,ignoring other peptide-presenting related steps.This may result in a gap between high prediction accuracy and relatively low clinical effectiveness.In this study,we designed an integrated in-silico pipeline,Neo-intline,which started from the SNPs and indels of the tumour samples to simulate the presentation process of peptides in-vivo through an integrated calculation model.Validation on the benchmark dataset of TESLA and clinically validated neoantigens illustrated that neo-intline could outperform current state-of-the-art tools on both sample level and melanoma level.Furthermore,by taking the mouse melanoma model as an example,we verified the effectiveness of 20 neoantigens,including 10 MHC-I and 10 MHC-II peptides.The in-vitro and in-vivo experiments showed that both peptides predicted by Neo-intline could recruit corresponding CD4^(+)T cells and CD8^(+)T cells to induce a T-cell-mediated cellular immune response.Moreover,although the therapeutic effect of neoantigen vaccines alone is not sufficient,combinations with other specific therapies,such as broad-spectrum immune-enhanced adjuvants of granulocyte-macrophage colony-stimulating factor(GM-CSF)and polyinosinic-polycytidylic acid(poly(I:C)),or immune checkpoint inhibitors,such as PD-1/PD-L1 antibodies,can illustrate significant anticancer effects on melanoma.Neo-intline can be used as a benchmark process for the design and screening of immunogenic targets for neoantigen vaccines.
基金We would like to thank Dr.Yongzhen Zhang from Shanghai Public Health Clinical Center,Fudan University,Shanghai,China,and Dr.Zhengli Shi from the Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan,China,for providing the genome sequence of 2019-nCoV collected from Wuhan,China.This work is supported in part by grants from National Key R&D Program of China(2017YFC0908400,2017YFC1700200)National Natural Science Foundation of China(31900483).
文摘Recently,a new type of unknown virus causing severe acute res-piratory infection was reported in Wuhan city,Hubei province,China(WHO,2020b).Infection of this virus was first reported in December 2019,and origin of the virus was traced back to a large seafood/wide animal market in Wuhan city.The serious clinical symptoms of the viral infection,including fever,dry cough,dys-pnea,and pneumonia,may result in progressive respiratory failure and even death.Moreover,the quick spread of the virus has caused an epidemic in China,as well as infection cases worldwide.The whole-genome sequence of Wuhan new virus(WH-Human_.1)was first released on January 10,2020(Zhang,2020),followed by additional ones released in Global Initiative on Sharing All Influ-enza Data(GISAID)(Shu and McCauley,2017).Later,this new virus was determined and announced as a new type of coronavirus(CoV;2019-nCoV)by the World Health Organization(WHO,2020a).
