Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1 - Short report

Sep 21, 2026

Human leukocyte antigen (HLA) restriction complicates conventional T-cell targeting for patients with diverse HLA backgrounds. Atypical MR1-restricted T-cells, distinct from MAIT cells, were identified as recognizing MR1-presented cancer-specific metabolites. This study tests whether the MC.7.G5 MR1T clone can serve as a pan-cancer, pan-population immunotherapy in pediatric settings. Bulk RNA sequencing and in vitro models evaluate MR1 expression, with embryonal tumors showing lower MR1 and limited activity; susceptibility appears in pediatric leukemia and diffuse midline glioma, suggesting improved survival potential.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages9

Reading Time23 min

AccessFree to download

Abstract

Introduction

Open access Short report Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1 Annelisa M. Cornel ,1,2 Loutje van der Sman,1,2 Jip T van Dinter,2 Marta Arrabito,2,3 Ester Dunnebach,1,2 Marliek van Hoesel,1 Thomas A Kluiver,1 Ana P Lopes,1 Noël M M Dautzenberg,2 Linde Dekker,2 Jorik M van Rijn,2 Denise A M H van den Beemt,1 Juliane L Buhl,2,4 Aimee du Chatinier,2 Farnaz Barneh,2 Yuyan Lu,2 Luca Lo Nigro,3 Anja Krippner-Heidenreich,2 Zsolt Sebestyén,1 Jurgen Kuball ,1,5 Esther Hulleman,2 Jarno Drost,2,4 Sebastiaan van Heesch,2 Olaf T Heidenreich,2 Weng Chuan Peng,2 Stefan Nierkens1,2 To cite: Cornel AM, van der Sman L, van Dinter JT, et al. Targeting pediatric cancers via T-cell recognition of themonomorphic MHC class Irelated protein MR1 . Journal for ImmunoTherapy of Cancer 2024;12:e007538 . doi:10 . 1136/ jitc-2023-007538 ► Additional supplemental material is published online only. To view, please visit the journal online ([http://dx.doi.org/10](http://dx.doi.org/10) . 1136/jitc-2023-007538) . Accepted 18 December 2023 © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. For numbered affiliations see end of article. Correspondence to Dr Stefan Nierkens; S. Nierkens-2@ [prinsesmaximacentrum.nl](prinsesmaximacentrum.nl) ABSTRACT 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. Asubpopulation of atypical, major histocompatibility complex-I related protein 1 (MR1)-restricted T-cells, distinctive from mucosal-associated invariant Tcells (MAITs), was recently identified recognizing currently unidentified MR1-presented cancerspecific 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. INTRODUCTION Unconventional T-cell populations that recognize their ligand beyond the context of major histocompatibility complexes (MHC) are increasingly recognized for their potential in cellular cancer immunotherapy. Examples of unconventional T-cell populations include invariant NKT-cells (iNKT), γδ T-cells, mucosal-associated invariant T-cells (MAIT), and MR1T-cells. Unlike conventional T-cells, which rely on polymorphic MHC molecules for target recognition, these unconventional T-cells recognize their cognate target in the context of monomorphic MHC-like molecules. 1 This majorly decreases the

FAQs

Why is conventional T-cell targeting complex for cancer patients?

Conventional T-cell targeting is HLA restricted, creating complexity when generating therapies for patients with diverse HLA backgrounds.

What distinguishes MR1T-cells from MAIT cells?

MR1T-cells are MR1-restricted and are distinct from MAIT cells, recognizing MR1-presented cancer-specific metabolites rather than MAIT-associated bacterial vitamin-derived metabolites.

What did the study find about MR1 expression and treatment susceptibility in pediatric tumors?

MR1 expression varied widely across pediatric tumor entities, with embryonal tumors showing significantly lower MR1 and most screened embryonal tumors resistant in vitro. Susceptibility was observed particularly in pediatric leukemia and diffuse midline glioma models.

Sep 21, 2026

Uploaded by Lucas Martin