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http://hdl.handle.net/2445/193235
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DC Field | Value | Language |
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dc.contributor.author | Elez, Elena | - |
dc.contributor.author | Mulet-Margalef, Núria | - |
dc.contributor.author | Sanso, Miriam | - |
dc.contributor.author | Ruiz-Pace, Fiorella | - |
dc.contributor.author | Mancuso, Francesco Mattia | - |
dc.contributor.author | Comas, Raquel | - |
dc.contributor.author | Ros, Javier | - |
dc.contributor.author | Argilés, Guillem | - |
dc.contributor.author | Martini, Giulia | - |
dc.contributor.author | Sanz-Garcia, Enrique | - |
dc.contributor.author | Baraibar, Iosune | - |
dc.contributor.author | Salvà, Francesc | - |
dc.contributor.author | Noguerido, Alba | - |
dc.contributor.author | Cuadra-Urteaga, José Luis | - |
dc.contributor.author | Fasani, Roberta | - |
dc.contributor.author | Garcia, Ariadna | - |
dc.contributor.author | Jimenez, José | - |
dc.contributor.author | Aguilar, Susana | - |
dc.contributor.author | Landolfi, Stefania | - |
dc.contributor.author | Hernández-Losa, Javier | - |
dc.contributor.author | Braña, Irene | - |
dc.contributor.author | Nuciforo, Paolo | - |
dc.contributor.author | Dienstmann, Rodrigo | - |
dc.contributor.author | Tabernero Caturla, Josep | - |
dc.contributor.author | Salazar Soler, Ramón | - |
dc.contributor.author | Vivancos, Ana | - |
dc.date.accessioned | 2023-02-07T15:57:58Z | - |
dc.date.available | 2023-02-07T15:57:58Z | - |
dc.date.issued | 2022-12-21 | - |
dc.identifier.issn | 1661-6596 | - |
dc.identifier.uri | http://hdl.handle.net/2445/193235 | - |
dc.description.abstract | The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial. | - |
dc.format.extent | 13 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | MDPI | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.3390/ijms24010118 | - |
dc.relation.ispartof | International Journal of Molecular Sciences, 2022, vol. 24, num. 1, p. 118 | - |
dc.relation.uri | https://doi.org/10.3390/ijms24010118 | - |
dc.rights | cc-by (c) Elez, Elena et al., 2022 | - |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.source | Articles publicats en revistes (Ciències Clíniques) | - |
dc.subject.classification | Càncer colorectal | - |
dc.subject.classification | Immunoteràpia | - |
dc.subject.classification | Marcadors bioquímics | - |
dc.subject.other | Colorectal cancer | - |
dc.subject.other | Immunotheraphy | - |
dc.subject.other | Biochemical markers | - |
dc.title | A comprehensive biomarker analysis of microsatellite unstable/mismatch repair deficient colorectal cancer cohort treated with immunotherapy | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 728844 | - |
dc.date.updated | 2023-02-07T15:57:58Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 36613564 | - |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) Articles publicats en revistes (Ciències Clíniques) |
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728844.pdf | 1.43 MB | Adobe PDF | View/Open |
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