RT Journal Article
SR Electronic
T1 Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e007538
DO 10.1136/jitc-2023-007538
VO 12
IS 3
A1 Cornel, Annelisa M.
A1 van der Sman, Loutje
A1 van Dinter, Jip T
A1 Arrabito, Marta
A1 Dunnebach, Ester
A1 van Hoesel, Marliek
A1 Kluiver, Thomas A
A1 Lopes, Ana P
A1 Dautzenberg, Noël M M
A1 Dekker, Linde
A1 van Rijn, Jorik M
A1 van den Beemt, Denise A M H
A1 Buhl, Juliane L
A1 du Chatinier, Aimee
A1 Barneh, Farnaz
A1 Lu, Yuyan
A1 Lo Nigro, Luca
A1 Krippner-Heidenreich, Anja
A1 Sebestyén, Zsolt
A1 Kuball, Jurgen
A1 Hulleman, Esther
A1 Drost, Jarno
A1 van Heesch, Sebastiaan
A1 Heidenreich, Olaf T
A1 Peng, Weng Chuan
A1 Nierkens, Stefan
YR 2024
UL http://jitc.bmj.com/content/12/3/e007538.abstract
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.