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Finding neoepitopes in mouse models of personalized cancer immunotherapy

Frontiers in Biology 2016年第5期11卷 366-375页

作者： sahar al seesi alok Das Mohapatra Arpita Pawashe Ion I. Mandoiu Fei Duan Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center University of Connecticut Cancer Center Farmington CT 06030 USA Department of Computer Science & Engineering University of Connecticut Storrs CT 06269 USA

BACKGROUND： Cancer immunotherapy uses one＇s own immune system to fight cancerous cells. As immune system is hard- wired to distinguish self and non-self, cancer immunotherapy is predicted to target cancerous cells specifically, therefore is less toxic than chemotherapy and radiation therapy, two major treatments for cancer. Cancer immunologists have spent decades to search for the specific targets in cancerous cells. METHODS： Due to the recent advances in high throughput sequencing and bioinformatics, evidence has merged that the neoantigens in cancerous cells are probably the cancer-specific targets that lead to the destruction of cancer. We will review the transplantable murine tumor models for cancer immunotherapy and the bioinformatics tools used to navigate mouse genome to identify tumor-rejecting neoantigens. RESULTS： Several groups have independently identified point mutations that can be recognized by T cells of host immune system. It is consistent with the note that the formation ofpeptide-MHC I-TCR complex is critical to activate T cells. Both anchor residue and TCR-facing residue mutations have been reported. While TCR-facing residue mutations may directly activate specific T cells, anchor residue mutations improve the binding of peptides to MHC I molecules, which increases the presentation of peptides and the T cell activation indirectly. CONCLUSIONS： Our work indicates that the affinity of neoepitopes for MHC I is not a predictor for anti-tumor immune responses in mice. Instead differential agretopic index （DAI）, the numerical difference of epitope-MHC I affinities between the mutated and un-mutated sequences is a significant predictor. A similar bioinformatics pipeline has been developed to generate personalized vaccines to treat human ovarian cancer in a Phase I clinical trial.

关键词： cancer immunotherapy tumor antigens neoantigens neoepitopes differential agretopic index (DAI) RNA-Seq single nucleotide variant (SNV)

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Effects of maternal nutrition on the expression of genomic imprinted genes inovine fetuses

Effects of maternal nutrition on the expression of genomic i...

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第十四届中国实验动物科学年会

作者： Jingyue (Ellie) Duan 张名媛 Kaleigh Flock sahar al seesi Ion Mandoiu Amanda Jones Elizabeth Johnson Sambhu Pillai Maria Hoffman Katelyn McFadden Hesheng Jiang Sarah Reed Kristen Govoni Steve Zinn Zongliang Jiang Xiuchun (Cindy) Tian Department of Animal Science University of Connecticut College of Animal Science and Technology Guangxi University Laboratory Animal Center Guangxi Medical University Department of Computer Science University of Connecticut School of Animal Science Louisiana StateUniversity Agricultural Center

Genomic imprinting is an epigenetic phenomenon of differential allelic expression based on parentalorigin. To date, 263 imprinted genes have been identified among all investigated mammalian ***, only 21 have been described in sheep, of which 11 are annotated in the current ovinegenome. Here, we aimtoi) use DNA/RNA high throughput sequencing to identify new monoallelicallyexpressed and imprinted genes in day 135 ovine fetuses and ii) determine whether maternal diet(100%, 60%, or 140% of National Research Council Total Digestible Nutrients) influences expression ofimprinted genes. We also reported strategies to solve technical challenges in the data analysispipeline. We identified 80 monoallelically expressed, 13 new putative imprinted genes, and fiveknown imprinted genes in sheep using the 263 genes stated above as a guide. Sanger sequencingconfirmed allelic expression of seven genes, CASD1, COPG2, DIRAS3, INPP5 F, PLAGL1, PPP1 R9 A, and SLC22 A18. Among the 13 putative imprinted genes, five were localized in the known sheep imprintingdomains of MEST on chromosome 4, DLK1/GTL2 on chromosome 18 and KCNQ1 on chromosome 21,and three were in a novel sheep imprinted cluster on chromosome 4, known in other species asPEG10/SGCE. The expression of DIRAS3, IGF2, PHLDA2, and SLC22 A18 was altered by maternal diet,albeit without allelic expression reversal. Together, our results expanded the list of sheep imprintedgenes to 34 and demonstrated that while the expression levels of four imprinted genes were changedby maternal diet, the allelic expression patterns were un-changed for all imprinted genes studied.

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