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.

Mennonna, D., Maccalli, C., Romano, M., Garavaglia, C., Capocefalo, F., Bordoni, R., et al. (2017). T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes. GUT, 66(3), 454-463 [10.1136/gutjnl-2015-309453].

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

Braga, Marco;
2017

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.
Si
Articolo in rivista - Articolo scientifico
Scientifica
antigens; Cancer immunobiology; colorectal cancer; gene mutation; immune response; Adenomatous Polyposis Coli Protein; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Cycle Proteins; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; DNA Mutational Analysis; DNA, Complementary; Epitopes, T-Lymphocyte; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Gene Expression; HLA Antigens; High-Throughput Screening Assays; Humans; Neoplastic Stem Cells; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins p21(ras); Smad4 Protein; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases; Gastroenterology
English
GUT
454
463
10
Mennonna, D., Maccalli, C., Romano, M., Garavaglia, C., Capocefalo, F., Bordoni, R., et al. (2017). T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes. GUT, 66(3), 454-463 [10.1136/gutjnl-2015-309453].
Mennonna, D; Maccalli, C; Romano, M; 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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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/219075
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