ABSTRACT
Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer patients. Here, we discovered that the novel immune checkpoint VISTA is highly expressed on a variety of tumor-infiltrating immune cells, especially myeloid derived suppressor cells (MDSCs) and CD8+ T cells. Then, peptide C1 with binding affinity to VISTA was developed by phage displayed bio-panning technique, and its mutant peptide VS3 was obtained by molecular docking based mutation. Peptide VS3 could bind VISTA with high affinity and block its interaction with ligand PSGL-1 under acidic condition, and elicit anti-tumor activity in vivo. The peptide DVS3-Pal was further designed by d-amino acid substitution and fatty acid modification, which exhibited strong proteolytic stability and significant anti-tumor activity through enhancing CD8+ T cell function and decreasing MDSCs infiltration. This is the first study to develop peptides to block VISTA/PSGL-1 interaction, which could act as promising candidates for cancer immunotherapy.
ABSTRACT
Objective To understand the trends of the prevalence of hyperuricemia of urbanized community residents Sijiqing Streets in Jianggan district in Hangzhou in the past 4 years,and analyze the correlation between hyperuricemia and metabolic factors,which provide scientific endence for prevention and treatment of hyperuricemia in communities.Methods 1 670 cases equal to or greater than 20 years old were randomly selected to analyze the trends of the prevalence of hyperuricemia in the past 4 consecutive years,which from urbanized community physical examination in 2010 to 2013 (male 749 cases,female 921 cases).Comparative analysis of age,BMI,waist circumference,systolic blood pressure,diastolic blood pressure,fasting blood glucose,glycosylated hemoglobin (HbA1C),TG,TC,LDL-C,and HDL-C levels between hyperuricemia group(male 264 cases,female 181 cases) and non hyperuricemia group (male 485 cases,female 740 cases) on 2013,and analyze the related metabolic factors to hyperuricemia by using non conditional logistic regression analysis.Results ①From 2010 to 2013,male hyperuricemia prevalence rates were 27.9％ (209/749,standardized rates were 27.4％)、29.1％ (218/749,standardized rates were 27.9％),33.2％ (249/749,standardized rates were 31.8％) and 35.2％ (264/749,standardized rates were 32.9％).The prevalence rates of female were 12.6％ (116/921,standardized rates were 11.7％),13.5％ (124/921,standardized rates were 11.9％),18.0％ (166/921,standardized rates were 15.7％) and 19.7(181/921,standardized rates were 17.2％),showed a increased tends year by year (the x2 of tends of male and female were 11.907 and 22.759,respectively,all P ＜ 0.01).In age stratified,the prevalence of hyperuricemia in middle and elder age group were increased significantly (the x2 of middle and elder aged man were 4.387、8.545,The x2 of middle and elder aged woman were 12.043、12.274,all P ＜ 0.05).The annual rate of male was higher than female (the x2 were 61.764、62.060、51.241、51.393,respectively,all P ＜ 0.01).② The male and female hyperuricemia group of age,BMI,waist circumference,systolic blood pressure,diastolic blood pressure,TG,TC,LDL-C levels were higher than those in non hyperuricemia group (the t of male were-2.052,-8.624,-8.772,-3.932,-4.380,-5.006,-3.564,-3.834,respectively; The t of female were-6.021,-8.839,-7.586,-4.702,-4.431,-6.334,-5.317,-5.119,respectively,all P ＜ 0.01),HDL-C levels were lower than those of non hyperuricemia group(the t of male and female were 6.097 and 3.170,respectively,all P ＜ 0.01),fasting blood glucose,HbA1c levels of non hyperuricemia group in female were also higher than the non hyperuricemia group (t =-2.750,-3.711,all P ＜ 0.01),however,Nor was statistical significance in male between the two groups (t =0.432,1.315,all P ＞ 0.05).③The non conditional Logistic regression analysis showed that,independent risk factor for male hyperuricemia were overweight (OR:2.151,95％ CI:1.439-3.215) or obese (OR:2.882,95％ CI:1.541-5.389),hypertension (OR:1.564,95％ CI:1.100 -2.224),dyslipidemia (OR:1.678,95 ％ CI:1.165-2.417) and abdominal obesity (OR:1.708,95 ％ CI:1.146-2.547),independent risk factors for hyperuricemia in women were overweight (OR:2.067,95％ CI:1.290-3.313) or obese (OR:2.843,95％ CI:1.523-5.309),hypertension (OR:1.530,95％ CI:1.042-2.248),dyslipidemia (OR:1.784,95 ％ CI:1.191-2.672) and hyperglycemia (OR:1.768,95％ CI:1.221-2.561).Conclusions The community people have a higher prevalence of hyperuricemia,which showed a increased trend,especially in the middle and old age year by year; overweight or obesity,abdominal obesity,hypertension and dyslipidaemia influence male prevalence rate of hyperurieemia,overweight or obesity,hypertension,hyperglycemia and dyslipidemia influence female prevalence rate of hyperuricemia,we should strengthen the comprehensive prevention and treatment of hyperuricemia in this community.