PT - JOURNAL ARTICLE AU - Cornel, Annelisa M. AU - van der Sman, Loutje AU - van Dinter, Jip T AU - Arrabito, Marta AU - Dunnebach, Ester AU - van Hoesel, Marliek AU - Kluiver, Thomas A AU - Lopes, Ana P AU - Dautzenberg, Noël M M AU - Dekker, Linde AU - van Rijn, Jorik M AU - van den Beemt, Denise A M H AU - Buhl, Juliane L AU - du Chatinier, Aimee AU - Barneh, Farnaz AU - Lu, Yuyan AU - Lo Nigro, Luca AU - Krippner-Heidenreich, Anja AU - Sebestyén, Zsolt AU - Kuball, Jurgen AU - Hulleman, Esther AU - Drost, Jarno AU - van Heesch, Sebastiaan AU - Heidenreich, Olaf T AU - Peng, Weng Chuan AU - Nierkens, Stefan TI - Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1 AID - 10.1136/jitc-2023-007538 DP - 2024 Mar 01 TA - Journal for ImmunoTherapy of Cancer PG - e007538 VI - 12 IP - 3 4099 - http://jitc.bmj.com/content/12/3/e007538.short 4100 - http://jitc.bmj.com/content/12/3/e007538.full SO - J Immunother Cancer2024 Mar 01; 12 AB - Human leukocyte antigen (HLA) restriction of conventional T-cell targeting introduces complexity in generating T-cell therapy strategies for patients with cancer with diverse HLA-backgrounds. A subpopulation of atypical, major histocompatibility complex-I related protein 1 (MR1)-restricted T-cells, distinctive from mucosal-associated invariant T-cells (MAITs), was recently identified recognizing currently unidentified MR1-presented cancer-specific metabolites. It is hypothesized that the MC.7.G5 MR1T-clone has potential as a pan-cancer, pan-population T-cell immunotherapy approach. These cells are irresponsive to healthy tissue while conferring T-cell receptor(TCR) dependent, HLA-independent cytotoxicity to a wide range of adult cancers. Studies so far are limited to adult malignancies. Here, we investigated the potential of MR1-targeting cellular therapy strategies in pediatric cancer. Bulk RNA sequencing data of primary pediatric tumors were analyzed to assess MR1 expression. In vitro pediatric tumor models were subsequently screened to evaluate their susceptibility to engineered MC.7.G5 TCR-expressing T-cells. Targeting capacity was correlated with qPCR-based MR1 mRNA and protein overexpression. RNA expression of MR1 in primary pediatric tumors varied widely within and between tumor entities. Notably, embryonal tumors exhibited significantly lower MR1 expression than other pediatric tumors. In line with this, most screened embryonal tumors displayed resistance to MR1T-targeting in vitro. MR1T susceptibility was observed particularly in pediatric leukemia and diffuse midline glioma models. This study demonstrates potential of MC.7.G5 MR1T-cell immunotherapy in pediatric leukemias and diffuse midline glioma, while activity against embryonal tumors was limited. The dismal prognosis associated with relapsed/refractory leukemias and high-grade brain tumors highlights the promise to improve survival rates of children with these cancers.Data are available in a public, open access repository. CPM for MR1, HLA-A, HLA-B, and HLA-C genes were retrieved via the Princess Máxima Center Biobank and Data Access Committee (BDAC) (EGAC00001001864). The code and data used in the analyses are available via https://github.com/VanHeeschLab/Cornel_et_al_2023. The single cell RNA sequencing data from the two analyzed hepatoblastoma organoids are available via ref.40 Data of functional assays is available upon request.