2026-04-17T01:32:14Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1932352025-12-05T13:12:27Zcom_2072_1057col_2072_478798col_2072_478916col_2072_478917

urn:hdl:2445/193235 A comprehensive biomarker analysis of microsatellite unstable/mismatch repair deficient colorectal cancer cohort treated with immunotherapy 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 Càncer colorectal Immunoteràpia Marcadors bioquímics Colorectal cancer Immunotheraphy Biochemical markers 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. 2023-02-07T15:57:58Z 2023-02-07T15:57:58Z 2022-12-21 2023-02-07T15:57:58Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.3390/ijms24010118 International Journal of Molecular Sciences, 2022, vol. 24, num. 1, p. 118 https://doi.org/10.3390/ijms24010118 cc-by (c) Elez, Elena et al., 2022 https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess MDPI Articles publicats en revistes (Ciències Clíniques)