Elez, ElenaMulet-Margalef, NúriaSanso, MiriamRuiz-Pace, FiorellaMancuso, Francesco MattiaComas, RaquelRos, JavierArgilés, GuillemMartini, GiuliaSanz-Garcia, EnriqueBaraibar, IosuneSalvà, FrancescNoguerido, AlbaCuadra-Urteaga, José LuisFasani, RobertaGarcia, AriadnaJimenez, JoséAguilar, SusanaLandolfi, StefaniaHernández-Losa, JavierBraña, IreneNuciforo, PaoloDienstmann, RodrigoTabernero Caturla, JosepSalazar Soler, RamónVivancos, Ana2023-02-072023-02-072022-12-211661-6596https://hdl.handle.net/2445/193235The 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.13 p.application/pdfengcc-by (c) Elez, Elena et al., 2022https://creativecommons.org/licenses/by/4.0/Càncer colorectalImmunoteràpiaMarcadors bioquímicsColorectal cancerImmunotheraphyBiochemical markersinfo:eu-repo/semantics/article7288442023-02-07info:eu-repo/semantics/openAccess36613564