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Title: | A comprehensive biomarker analysis of microsatellite unstable/mismatch repair deficient colorectal cancer cohort treated with immunotherapy |
Author: | Elez, Elena Mulet-Margalef, Núria Sanso, Miriam Ruiz-Pace, Fiorella Mancuso, Francesco Mattia Comas, Raquel Ros, Javier Argilés, Guillem Martini, Giulia Sanz-Garcia, Enrique Baraibar, Iosune Salvà, Francesc Noguerido, Alba Cuadra-Urteaga, José Luis Fasani, Roberta Garcia, Ariadna Jimenez, José Aguilar, Susana Landolfi, Stefania Hernández-Losa, Javier Braña, Irene Nuciforo, Paolo Dienstmann, Rodrigo Tabernero Caturla, Josep Salazar Soler, Ramón Vivancos, Ana |
Keywords: | Càncer colorectal Immunoteràpia Marcadors bioquímics Colorectal cancer Immunotheraphy Biochemical markers |
Issue Date: | 21-Dec-2022 |
Publisher: | MDPI |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.3390/ijms24010118 |
It is part of: | International Journal of Molecular Sciences, 2022, vol. 24, num. 1, p. 118 |
URI: | http://hdl.handle.net/2445/193235 |
Related resource: | https://doi.org/10.3390/ijms24010118 |
ISSN: | 1661-6596 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) Articles publicats en revistes (Ciències Clíniques) |
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