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T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes.

T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes.
Author Information (click to view)

Mennonna D, Maccalli C, Romano MC, Garavaglia C, Capocefalo F, Bordoni R, Severgnini M, De Bellis G, Sidney J, Sette A, Gori A, Longhi R, Braga M, Ghirardelli L, Baldari L, Orsenigo E, Albarello L, Zino E, Fleischhauer K, Mazzola G, Ferrero N, Amoroso A, Casorati G, Parmiani G, Dellabona P,


Mennonna D, Maccalli C, Romano MC, Garavaglia C, Capocefalo F, Bordoni R, Severgnini M, De Bellis G, Sidney J, Sette A, Gori A, Longhi R, Braga M, Ghirardelli L, Baldari L, Orsenigo E, Albarello L, Zino E, Fleischhauer K, Mazzola G, Ferrero N, Amoroso A, Casorati G, Parmiani G, Dellabona P, (click to view)

Mennonna D, Maccalli C, Romano MC, Garavaglia C, Capocefalo F, Bordoni R, Severgnini M, De Bellis G, Sidney J, Sette A, Gori A, Longhi R, Braga M, Ghirardelli L, Baldari L, Orsenigo E, Albarello L, Zino E, Fleischhauer K, Mazzola G, Ferrero N, Amoroso A, Casorati G, Parmiani G, Dellabona P,

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Gut 2015 12 1766(3) 454-463 doi 10.1136/gutjnl-2015-309453

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.

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