T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes. Issue 3 (17th December 2015)

• Record Type: Journal Article
• Authors: Mennonna, Daniele; Maccalli, Cristina; Romano, Michele C; Garavaglia, Claudio; Capocefalo, Filippo; Bordoni, Roberta; Severgnini, Marco; De Bellis, Gianluca; Sidney, John; Sette, Alessandro; Gori, Alessandro; Longhi, Renato; Braga, Marco; Ghirardelli, Luca; Baldari, Ludovica; Orsenigo, Elena; Albarello, Luca; Zino, Elisabetta; Fleischhauer, Katharina; Mazzola, Gina; Ferrero, Norma; Amoroso, Antonio; Casorati, Giulia; Parmiani, Giorgio; Dellabona, Paolo
• Is Part Of: Gut. Volume 66:Issue 3(2017)
• Page Start: 454
• Page End: 463
• Publication Date: 2015-12-17
• Subjects: CANCER IMMUNOBIOLOGY -- ANTIGENS -- COLORECTAL CANCER -- GENE MUTATION -- IMMUNE RESPONSE; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2015-309453
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: Patient-specific (unique) tumour antigens, encoded by somatically mutated cancer genes, generate neoepitopes that are implicated in the induction of tumour-controlling T cell responses. Recent advancements in massive DNA sequencing combined with robust T cell epitope predictions have allowed their systematic identification in several malignancies. Design: We undertook the identification of unique neoepitopes in colorectal cancers (CRCs) by using high-throughput sequencing of cDNAs expressed by standard cancer cell cultures, and by related cancer stem/initiating cells (CSCs) cultures, coupled with a reverse immunology approach not requiring human leukocyte antigen (HLA) allele-specific epitope predictions. Results: Several unique mutated antigens of CRC, shared by standard cancer and related CSC cultures, were identified by this strategy. CD8 + and CD4 + T cells, either autologous to the patient or derived from HLA-matched healthy donors, were readily expanded in vitro by peptides spanning different cancer mutations and specifically recognised differentiated cancer cells and CSC cultures, expressing the mutations. Neoepitope-specific CD8 + T cell frequency was also increased in a patient, compared with healthy donors, supporting the occurrence of clonal expansion in vivo. Conclusions: These results provide a proof-of-concept approach for the identification of unique neoepitopes that are immunogenic in patients with CRC and can also target T cells against the most aggressive CSC component.