Discovery and validation of frameshift-derived neopeptides in Lynch syndrome: paving the way for novel cancer prevention strategies
Background Lynch syndrome (LS), caused by germline pathogenic variants in the mismatch repair genes, leads to high rates of frameshift-derived neopeptide (FSDN) expression due to microsatellite instability (MSI). While colorectal cancer (CRC) prevention is effective, most LS-related tumors lack such...
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BMJ Publishing Group
2025-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/4/e011177.full |
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| author | Marta Pineda Sabela Carballal María Pellisé Liseth Rivero Francesc Balaguer Fátima Marín Leticia Moreira Teresa Ocaña Manel Juan Daniel Benitez-Ribas Georgina Flórez-Grau Joaquín Castillo-Iturra Cristina Bayó Giancarlo Castellano Hardeep Kumari Maria Daca-Alvarez Oswaldo Ortiz Rebeca Moreira Julia Canet-Hermida Capella Gabriel |
| author_facet | Marta Pineda Sabela Carballal María Pellisé Liseth Rivero Francesc Balaguer Fátima Marín Leticia Moreira Teresa Ocaña Manel Juan Daniel Benitez-Ribas Georgina Flórez-Grau Joaquín Castillo-Iturra Cristina Bayó Giancarlo Castellano Hardeep Kumari Maria Daca-Alvarez Oswaldo Ortiz Rebeca Moreira Julia Canet-Hermida Capella Gabriel |
| author_sort | Marta Pineda |
| collection | DOAJ |
| description | Background Lynch syndrome (LS), caused by germline pathogenic variants in the mismatch repair genes, leads to high rates of frameshift-derived neopeptide (FSDN) expression due to microsatellite instability (MSI). While colorectal cancer (CRC) prevention is effective, most LS-related tumors lack such strategies. Cancer vaccines targeting FSDNs offer a promising approach for immune interception in LS. This study aimed to identify and validate LS-related FSDNs to develop vaccines for cancer prevention.Methods We identified LS-related coding MS mutations and predicted FSDN with high coverage on common Human Leukocyte Antigen (HLA)-I and II alleles. We validated FSDN-associated mutations in colorectal adenomas (CrAD), endometrial cancers (EC), and CRC samples from patients with LS, non-LS tumors, and cell lines. Immunogenicity was assessed through interferon (IFN)-γ enzyme-linked immunospot and flow cytometry analysis of tissue-infiltrating lymphocytes (TILs) from LS carriers.Results We prioritized 53 HLA-I and 45 HLA-II FSDNs in MSI tumors using in silico predictions. Validation revealed 86.7% of FSDN-associated mutations present in LS-CRC samples, with a median of 7.67 (6.5–9) mutations in CrADs and 6.02 (2–10) in CRCs. Sequencing of CrAD and EC samples showed 95% and 77.5% of predicted FSDN-associated mutations, respectively. MSI cancer cell lines transcribed 69.8% of FSDNs. Immunogenicity assays showed that 71% of potential FSDNs elicited IFN-γ responses, with a median of 7.37 (1–10.75) HLA-I and 6 (2–5.75) HLA-II FSDNs per patient. After prioritizing 24 FSDN, in a cohort of 19 LS-derived samples (4 CrAD and 15 normal mucosa), 52% (10/19) demonstrated T-cell reactivity to an HLA-I neoantigen pool. CD8+CD137+ activation markers increased significantly (p=0.037) over time and peptide-specific cells were detected by pentamer staining.Conclusions Our predicted FSDN set has optimal coverage among LS carriers and can induce IFN-γ inflammatory responses in LS-derived TILs, offering an opportunity for vaccine development. |
| format | Article |
| id | doaj-art-bdc9f50eb7914f2aaffb195d3a542bc9 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-bdc9f50eb7914f2aaffb195d3a542bc92025-08-20T01:48:52ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-04-0113410.1136/jitc-2024-011177Discovery and validation of frameshift-derived neopeptides in Lynch syndrome: paving the way for novel cancer prevention strategiesMarta Pineda0Sabela Carballal1María Pellisé2Liseth Rivero3Francesc Balaguer4Fátima Marín5Leticia Moreira6Teresa Ocaña7Manel Juan8Daniel Benitez-Ribas9Georgina Flórez-Grau10Joaquín Castillo-Iturra11Cristina Bayó12Giancarlo Castellano13Hardeep Kumari14Maria Daca-Alvarez15Oswaldo Ortiz16Rebeca Moreira17Julia Canet-Hermida18Capella Gabriel191 Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, SpainInstitut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalunya, SpainDepartment of Gastroenterology, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Institut Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainGastroenterology, Hospital Clinic de Barcelona, Barcelona, Catalunya, SpainUniversitat de Barcelona, Barcelona, Spain1 Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d’Investigació Biomèdica de Bellvitge – IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L`Hospitalet de Llobregat, Barcelona, Spain2 Universitat de Barcelona, Barcelona, Spain1 Department of Gastroenterology, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Barcelona, SpainRed Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, SpainInstitut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalunya, SpainDepartment of Gastroenterology, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Institut Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainImmunology, Hospital Clinic de Barcelona, Barcelona, Catalunya, SpainInstitut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalunya, SpainInstitut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalunya, SpainInstitut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalunya, SpainInstitut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalunya, SpainInstitut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalunya, SpainHereditary Cancer Program, Catalan institute of oncology, IDIBELL, Badalona, Catalunya, SpainHereditary Cancer Program, Catalan institute of oncology, IDIBELL, Badalona, Catalunya, SpainBackground Lynch syndrome (LS), caused by germline pathogenic variants in the mismatch repair genes, leads to high rates of frameshift-derived neopeptide (FSDN) expression due to microsatellite instability (MSI). While colorectal cancer (CRC) prevention is effective, most LS-related tumors lack such strategies. Cancer vaccines targeting FSDNs offer a promising approach for immune interception in LS. This study aimed to identify and validate LS-related FSDNs to develop vaccines for cancer prevention.Methods We identified LS-related coding MS mutations and predicted FSDN with high coverage on common Human Leukocyte Antigen (HLA)-I and II alleles. We validated FSDN-associated mutations in colorectal adenomas (CrAD), endometrial cancers (EC), and CRC samples from patients with LS, non-LS tumors, and cell lines. Immunogenicity was assessed through interferon (IFN)-γ enzyme-linked immunospot and flow cytometry analysis of tissue-infiltrating lymphocytes (TILs) from LS carriers.Results We prioritized 53 HLA-I and 45 HLA-II FSDNs in MSI tumors using in silico predictions. Validation revealed 86.7% of FSDN-associated mutations present in LS-CRC samples, with a median of 7.67 (6.5–9) mutations in CrADs and 6.02 (2–10) in CRCs. Sequencing of CrAD and EC samples showed 95% and 77.5% of predicted FSDN-associated mutations, respectively. MSI cancer cell lines transcribed 69.8% of FSDNs. Immunogenicity assays showed that 71% of potential FSDNs elicited IFN-γ responses, with a median of 7.37 (1–10.75) HLA-I and 6 (2–5.75) HLA-II FSDNs per patient. After prioritizing 24 FSDN, in a cohort of 19 LS-derived samples (4 CrAD and 15 normal mucosa), 52% (10/19) demonstrated T-cell reactivity to an HLA-I neoantigen pool. CD8+CD137+ activation markers increased significantly (p=0.037) over time and peptide-specific cells were detected by pentamer staining.Conclusions Our predicted FSDN set has optimal coverage among LS carriers and can induce IFN-γ inflammatory responses in LS-derived TILs, offering an opportunity for vaccine development.https://jitc.bmj.com/content/13/4/e011177.full |
| spellingShingle | Marta Pineda Sabela Carballal María Pellisé Liseth Rivero Francesc Balaguer Fátima Marín Leticia Moreira Teresa Ocaña Manel Juan Daniel Benitez-Ribas Georgina Flórez-Grau Joaquín Castillo-Iturra Cristina Bayó Giancarlo Castellano Hardeep Kumari Maria Daca-Alvarez Oswaldo Ortiz Rebeca Moreira Julia Canet-Hermida Capella Gabriel Discovery and validation of frameshift-derived neopeptides in Lynch syndrome: paving the way for novel cancer prevention strategies Journal for ImmunoTherapy of Cancer |
| title | Discovery and validation of frameshift-derived neopeptides in Lynch syndrome: paving the way for novel cancer prevention strategies |
| title_full | Discovery and validation of frameshift-derived neopeptides in Lynch syndrome: paving the way for novel cancer prevention strategies |
| title_fullStr | Discovery and validation of frameshift-derived neopeptides in Lynch syndrome: paving the way for novel cancer prevention strategies |
| title_full_unstemmed | Discovery and validation of frameshift-derived neopeptides in Lynch syndrome: paving the way for novel cancer prevention strategies |
| title_short | Discovery and validation of frameshift-derived neopeptides in Lynch syndrome: paving the way for novel cancer prevention strategies |
| title_sort | discovery and validation of frameshift derived neopeptides in lynch syndrome paving the way for novel cancer prevention strategies |
| url | https://jitc.bmj.com/content/13/4/e011177.full |
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