Colorectal cancer patients-derived immunity-organoid platform unveils cancer-specific tissue markers associated with immunotherapy resistance
Colorectal cancer (CRC) is a devastating disease, ranking as the second leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors (ICIs) have emerged as promising treatments; however, their efficacy is largely restricted to a subgroup of microsatellite instable (MSI) CRCs. In contrast, microsatellite stable (MSS) CRCs, which account for the majority of cases, exhibit variable and generally weaker response to ICIs, with only a subset demonstrating exceptional responsiveness. Identifying novel cancer-specific tissue (CST) markers predictive of immunotherapy response is crucial for refining patient selection and overcoming treatment resistance. In this study, we developed clinically relevant CRC organoids and autologous immune system interaction platforms to model ICI response. We conducted a comprehensive molecular characterization of both responder and non-responder models, identifying CST markers that predict ICI response. Validation of these findings was performed using an independent cohort of patient specimens through multiplex immunofluorescence. Furthermore, we demonstrated that knocking out a key gene from the identified predictive signature in resistant organoids restored immune sensitivity and induced T-cell-mediated apoptosis. Overall, our results provide novel insights into the mechanisms underlying immunotherapy resistance and suggest new markers for enhancing patient selection. These findings may pave the way for new therapeutic options in MSS patients, potentially broadening the cohort of individuals eligible for immunotherapy.
Authors
- Stefano Ugel (ORCID: https://orcid.org/0000-0002-6639-7608)
- Carmine Carbone (ORCID: https://orcid.org/0000-0001-5168-747X)
- Enrico Gurreri (ORCID: https://orcid.org/0000-0002-7752-4641)
- Lorenzo Priori
- Alessia Caggiano
- Maria Alessandra Calegari (ORCID: https://orcid.org/0000-0001-6856-2593)
- Giuseppe Quero (ORCID: https://orcid.org/0000-0002-0001-9479)
- Vincenzo Corbo (ORCID: https://orcid.org/0000-0002-6340-8009)
- Lisa Salvatore (ORCID: https://orcid.org/0000-0003-3864-0719)
- Claudio Fiorillo (ORCID: https://orcid.org/0000-0001-7681-3567)
- Anna Ceccarelli
- Sergio Alfieri (ORCID: https://orcid.org/0000-0002-7813-4426)
- Maurizio Martini (ORCID: https://orcid.org/0000-0002-6260-6310)
- Alessandra Battaglia (ORCID: https://orcid.org/0000-0001-7179-8900)
- Giannicola Genovese (ORCID: https://orcid.org/0000-0003-1392-9954)
- Geny Piro (ORCID: https://orcid.org/0000-0003-3708-5397)
- Giampaolo Tortora (ORCID: https://orcid.org/0000-0002-1378-4962)
- Antonio De Agostini (ORCID: https://orcid.org/0000-0002-3910-0223)
- Serena Ascrizzi (ORCID: https://orcid.org/0000-0002-7741-4119)
- Giulia Scaglione (ORCID: https://orcid.org/0000-0002-9060-3854)
- Maria Bensi (ORCID: https://orcid.org/0000-0002-5647-0525)
- Andrea Fattorossi
- G. Trovato (ORCID: https://orcid.org/0009-0004-9526-0725)
- Francesco De Sanctis (ORCID: https://orcid.org/0000-0002-7232-7585)
- Annachiara Esposito (ORCID: https://orcid.org/0000-0002-5017-1954)
- MARIAGRAZIA MARATTA
Institutions
- Università Cattolica del Sacro Cuore (IT)
- University of Messina (IT)
- University of Verona (IT)
- The University of Texas MD Anderson Cancer Center (US)
- Agostino Gemelli University Polyclinic (IT)
- Istituto Ortopedico Gaetano Pini (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1038/s41419-024-07266-5
- Citations
- 16
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 4.52
Funders
- Sanofi
- Ministero della Salute
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- Sanofi Genzyme