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2022-12-21

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cc-by (c) Elez, Elena et al., 2022
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/193235

A comprehensive biomarker analysis of microsatellite unstable/mismatch repair deficient colorectal cancer cohort treated with immunotherapy

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https://doi.org/10.3390/ijms24010118

Resum

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.

Matèries

Càncer colorectal, Immunoteràpia, Marcadors bioquímics

Matèries (anglès)

Colorectal cancer, Immunotheraphy, Biochemical markers

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Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

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. A comprehensive biomarker analysis of microsatellite unstable/mismatch repair deficient colorectal cancer cohort treated with immunotherapy. _International Journal of Molecular Sciences_. 2022. Vol. 24, núm. 1, pàgs. 118. [consulta: 3 de febrer de 2026]. ISSN: 1661-6596. [Disponible a: https://hdl.handle.net/2445/193235]

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