PMID- 29441070 OWN - NLM STAT- MEDLINE DCOM- 20190228 LR - 20190228 IS - 1664-3224 (Print) IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 9 DP - 2018 TI - A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations. PG - 99 LID - 10.3389/fimmu.2018.00099 [doi] LID - 99 AB - The identification of recurrent human leukocyte antigen (HLA) neoepitopes driving T cell responses against tumors poses a significant bottleneck in the development of approaches for precision cancer therapeutics. Here, we employ a bioinformatics method, Prediction of T Cell Epitopes for Cancer Therapy, to analyze sequencing data from neuroblastoma patients and identify a recurrent anaplastic lymphoma kinase mutation (ALK R1275Q) that leads to two high affinity neoepitopes when expressed in complex with common HLA alleles. Analysis of the X-ray structures of the two peptides bound to HLA-B*15:01 reveals drastically different conformations with measurable changes in the stability of the protein complexes, while the self-epitope is excluded from binding due to steric hindrance in the MHC groove. To evaluate the range of HLA alleles that could display the ALK neoepitopes, we used structure-based Rosetta comparative modeling calculations, which accurately predict several additional high affinity interactions and compare our results with commonly used prediction tools. Subsequent determination of the X-ray structure of an HLA-A*01:01 bound neoepitope validates atomic features seen in our Rosetta models with respect to key residues relevant for MHC stability and T cell receptor recognition. Finally, MHC tetramer staining of peripheral blood mononuclear cells from HLA-matched donors shows that the two neoepitopes are recognized by CD8+ T cells. This work provides a rational approach toward high-throughput identification and further optimization of putative neoantigen/HLA targets with desired recognition features for cancer immunotherapy. FAU - Toor, Jugmohit S AU - Toor JS AD - Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. FAU - Rao, Arjun A AU - Rao AA AD - Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, United States. FAU - McShan, Andrew C AU - McShan AC AD - Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. FAU - Yarmarkovich, Mark AU - Yarmarkovich M AD - Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States. FAU - Nerli, Santrupti AU - Nerli S AD - Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. AD - Department of Computer Science, University of California, Santa Cruz, Santa Cruz, CA, United States. FAU - Yamaguchi, Karissa AU - Yamaguchi K AD - Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. FAU - Madejska, Ada A AU - Madejska AA AD - Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, United States. FAU - Nguyen, Son AU - Nguyen S AD - Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. FAU - Tripathi, Sarvind AU - Tripathi S AD - Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. FAU - Maris, John M AU - Maris JM AD - Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States. FAU - Salama, Sofie R AU - Salama SR AD - Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, United States. AD - Howard Hughes Medical Institute, University of California, Santa Cruz, Santa Cruz, CA, United States. FAU - Haussler, David AU - Haussler D AD - Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, United States. AD - Howard Hughes Medical Institute, University of California, Santa Cruz, Santa Cruz, CA, United States. FAU - Sgourakis, Nikolaos G AU - Sgourakis NG AD - Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. LA - eng GR - R35 GM125034/GM/NIGMS NIH HHS/United States GR - S10 OD021832/OD/NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - U54 HG007990/HG/NHGRI NIH HHS/United States GR - S10 OD018455/OD/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20180130 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Antigens, Neoplasm) RN - 0 (Epitopes) RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Peptides) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) SB - IM MH - Alleles MH - Amino Acid Sequence MH - Anaplastic Lymphoma Kinase/*genetics/*immunology/metabolism MH - Antigens, Neoplasm/*genetics/*immunology/metabolism MH - CD8-Positive T-Lymphocytes/immunology/metabolism MH - Computational Biology/methods MH - Epitopes/chemistry/*genetics/*immunology MH - Epitopes, T-Lymphocyte/chemistry/genetics/immunology MH - Histocompatibility Antigens Class I/chemistry/immunology/metabolism MH - Humans MH - Models, Molecular MH - *Mutation MH - Peptides/genetics/immunology/metabolism MH - Protein Conformation MH - Protein Multimerization MH - Structure-Activity Relationship PMC - PMC5797543 OTO - NOTNLM OT - MHC class I OT - T cell receptor OT - cancer OT - computational biology OT - human leukocyte antigens OT - neoepitopes OT - structural biology EDAT- 2018/02/15 06:00 MHDA- 2018/02/15 06:01 PMCR- 2018/01/01 CRDT- 2018/02/15 06:00 PHST- 2017/10/05 00:00 [received] PHST- 2018/01/12 00:00 [accepted] PHST- 2018/02/15 06:00 [entrez] PHST- 2018/02/15 06:00 [pubmed] PHST- 2018/02/15 06:01 [medline] PHST- 2018/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2018.00099 [doi] PST - epublish SO - Front Immunol. 2018 Jan 30;9:99. doi: 10.3389/fimmu.2018.00099. eCollection 2018.