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AutoEpiCollect,一种用于疫苗设计的新型基于机器学习的图形用户界面软件:在针对PIK3CA新抗原的泛癌疫苗设计中的应用。

AutoEpiCollect, a Novel Machine Learning-Based GUI Software for Vaccine Design: Application to Pan-Cancer Vaccine Design Targeting PIK3CA Neoantigens.

作者信息

Samudrala Madhav, Dhaveji Sindhusri, Savsani Kush, Dakshanamurthy Sivanesan

机构信息

College of Arts and Sciences, The University of Virginia, Charlottesville, VA 22903, USA.

College of Science, Virginia Tech, Blacksburg, VA 24061, USA.

出版信息

Bioengineering (Basel). 2024 Mar 27;11(4):322. doi: 10.3390/bioengineering11040322.

Abstract

Previous epitope-based cancer vaccines have focused on analyzing a limited number of mutated epitopes and clinical variables preliminarily to experimental trials. As a result, relatively few positive clinical outcomes have been observed in epitope-based cancer vaccines. Further efforts are required to diversify the selection of mutated epitopes tailored to cancers with different genetic signatures. To address this, we developed the first version of AutoEpiCollect, a user-friendly GUI software, capable of generating safe and immunogenic epitopes from missense mutations in any oncogene of interest. This software incorporates a novel, machine learning-driven epitope ranking method, leveraging a probabilistic logistic regression model that is trained on experimental T-cell assay data. Users can freely download AutoEpiCollectGUI with its user guide for installing and running the software on GitHub. We used AutoEpiCollect to design a pan-cancer vaccine targeting missense mutations found in the proto-oncogene PIK3CA, which encodes the p110ɑ catalytic subunit of the PI3K kinase protein. We selected PIK3CA as our gene target due to its widespread prevalence as an oncokinase across various cancer types and its lack of presence as a gene target in clinical trials. After entering 49 distinct point mutations into AutoEpiCollect, we acquired 361 MHC Class I epitope/HLA pairs and 219 MHC Class II epitope/HLA pairs. From the 49 input point mutations, we identified MHC Class I epitopes targeting 34 of these mutations and MHC Class II epitopes targeting 11 mutations. Furthermore, to assess the potential impact of our pan-cancer vaccine, we employed PCOptim and PCOptim-CD to streamline our epitope list and attain optimized vaccine population coverage. We achieved a world population coverage of 98.09% for MHC Class I data and 81.81% for MHC Class II data. We used three of our predicted immunogenic epitopes to further construct 3D models of peptide-HLA and peptide-HLA-TCR complexes to analyze the epitope binding potential and TCR interactions. Future studies could aim to validate AutoEpiCollect's vaccine design in murine models affected by PIK3CA-mutated or other mutated tumor cells located in various tissue types. AutoEpiCollect streamlines the preclinical vaccine development process, saving time for thorough testing of vaccinations in experimental trials.

摘要

以往基于表位的癌症疫苗主要集中在初步分析有限数量的突变表位和临床变量,然后开展实验性试验。因此,基于表位的癌症疫苗所观察到的阳性临床结果相对较少。需要进一步努力,使针对具有不同基因特征的癌症的突变表位选择更加多样化。为了解决这个问题,我们开发了第一版AutoEpiCollect,这是一款用户友好的图形用户界面软件,能够从任何感兴趣的癌基因中的错义突变产生安全且具有免疫原性的表位。该软件采用了一种新颖的、机器学习驱动的表位排序方法,利用在实验性T细胞检测数据上训练的概率逻辑回归模型。用户可以在GitHub上免费下载AutoEpiCollectGUI及其用户指南,用于在软件上进行安装和运行。我们使用AutoEpiCollect设计了一种泛癌疫苗,靶向原癌基因PIK3CA中发现的错义突变,该基因编码PI3K激酶蛋白的p110ɑ催化亚基。我们选择PIK3CA作为我们的基因靶点,是因为它作为一种致癌激酶在各种癌症类型中广泛存在,且在临床试验中尚未作为基因靶点。在将49个不同的点突变输入AutoEpiCollect后,我们获得了361个MHC I类表位/HLA对和219个MHC II类表位/HLA对。从49个输入的点突变中,我们鉴定出针对其中34个突变的MHC I类表位和针对11个突变的MHC II类表位。此外,为了评估我们的泛癌疫苗的潜在影响,我们使用PCOptim和PCOptim-CD来精简我们的表位列表,并实现优化的疫苗人群覆盖率。我们实现了MHC I类数据的全球人群覆盖率为98.09%,MHC II类数据的全球人群覆盖率为81.81%。我们使用三个预测的免疫原性表位进一步构建肽-HLA和肽-HLA-TCR复合物的三维模型,以分析表位结合潜力和TCR相互作用。未来的研究可以旨在在受PIK3CA突变或位于各种组织类型中的其他突变肿瘤细胞影响的小鼠模型中验证AutoEpiCollect的疫苗设计。AutoEpiCollect简化了临床前疫苗开发过程,为在实验性试验中全面测试疫苗节省了时间。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8a2f/11048108/e4373af28b1c/bioengineering-11-00322-g001.jpg

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