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The common neoantigens in colorectal cancer are predicted and validated to be presented or immunogenic

By Zhaoduan Liang, Lili Qin, Lei Chen, Wenhui Li, Chao Chen, Yaling Huang, Le Zhang, Songming Liu, Si Qiu, Yuping Ge, Wenting Peng, Xinxin Lin, Xuan Dong, Xiuqing Zhang, Bo Li

Posted 26 Jun 2019
bioRxiv DOI: 10.1101/682617

Colorectal cancer (CRC) is a malignant cancer with high incidence and mortality in the world, as the result of the traditional treatments. Immunotherapy targeting neoantigens can induce durable tumor regression in cancer patients, but is almost limited to individual treatment, resulting from the unique neoantigens. Many shared oncogenic mutations are detected, but whether the common neoantigens can be identified in CRC is unknown. Using the somatic mutations data from 321 CRC patients combined with a filter standard and 7 predicted algorithms, we screened and obtained 25 HLA-A*11:01 restricted common neoantigens with high binding affinity (IC50<50 nM) and presentation score (>0.9). Except the positive epitope KRAS_G12V8-16, 11 out of 25 common neoantigens were proved to be naturally processed and presented on constructed K562 cell surface by mass spectroscopy (MS), and 11 out of 25 common neoantigens specifically induced in vitro pre-stimulated cytotoxic lymphocyte (CTL) to secrete IFN-γ. However, only 2 out of 25 common neoantigens were simultaneously presented and immunogenic. Moreover, using cell-sorting technology combined with single-cell RNA sequencing, the immune repertoire profiles of C1orf170_S418G413-421 and KRAS_G12V8-16-specific CTL were clarified. Therefore, common neoantigens with presentation and immunogenicity could be found in CRC, which would be developed as the universal targets for CRC immunotherapy. * Abbreviations : CRC : colorectal cancer MMR : deficient mismatch repair MSI-H : highly microsatellite instable pMMR : proficient mismatch repair MSS : microsatellite stable ADC : autologous tumor lysate DC CAR : chimeric antigen receptor TAA : tumor associated antigen CEA : carcinoembryonic antigen HER2 : human epidermal growth factor receptor-2 TSA : tumor-specific antigen MHC : major histocompatibility complex TMB : tumor mutational burden TCR : T-cell receptor PRM : parallel reaction monitoring TIL : tumor infiltrating lymphocyte MS : mass spectrometry ATCC : American Type Culture Collection PBMC : peripheral blood mononuclear cell ICGC : International Cancer Genome Consortium COCA-CN : China-Colorectal Cancer Project InDel : insertions or deletion EPIC : Epitope Presentation Integrated prediction MITD : MHC class I trafficking signal CTL : cytotoxic lymphocyte ELISPOT : enzyme-linked immunospot FACS : fluorescence-activated cell sorting GEM : Gel Bead in Emulsion

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