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DNA barcoded peptide-MHC multimers to measure and monitor minor histocompatibility antigen-specific T cells after allogeneic stem cell transplantation

A recent study published in Journal for Immunotherapy of Cancer investigates the utility of DNA barcoded peptide-major histocompatibility complex (pMHC) multimers in detecting and monitoring minor histocompatibility antigen (MiHA)-specific T cells in patients undergoing HLA-matched allogeneic stem cell transplantation (alloSCT). Conducted by researchers at Leiden University Medical Center, the study aimed to understand the interplay between graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD) by characterizing antigen-specific immune responses in 16 patients who received donor lymphocyte infusions (DLI) after alloSCT.

In total, the authors screened 255 peptides, including 227 MiHAs and 93 viral antigens, using barcoded pMHC multimers to detect T-cell responses in peripheral blood mononuclear cells. Across the cohort, 88 unique T-cell responses targeting 49 MiHAs were identified, with 72.7% of these responses directed against mismatched MiHAs. T-cell frequencies varied widely, ranging from undetectable levels to 30.5% of CD8⁺ T cells. High T-cell frequencies (greater than 1% of CD8⁺ T cells) were observed in 12 patients, including nine with severe GvHD, two with limited GvHD, and one with no GvHD. Responses to non-mismatched MiHAs were lower in frequency, inconsistent, and typically unrelated to clinical outcomes. The study showed that T-cell responses against mismatched MiHAs peaked 6–8 weeks after DLI, coinciding with the onset of GvHD. These responses were sustained over time in 63.3% of mismatched MiHAs, as measured in multiple post-DLI samples, compared to only 21.4% for non-mismatched MiHAs.

This study highlights the immunodominance of certain MiHAs and underscores the value of barcoded pMHC multimers as a scalable and precise tool for monitoring antigen-specific immune responses. Overall, this method provides critical insights into the dynamics of T-cell expansion and tissue specificity, enabling better predictions of GvL and GvHD outcomes. By identifying dominant MiHAs and their role in immune responses, this approach could inform patient-specific alloSCT strategies, such as optimizing donor selection or tailoring immunotherapy to minimize GvHD while preserving GvL efficacy. These findings pave the way for integrating barcoded pMHC multimers into clinical practice, offering a robust platform for immune monitoring in alloSCT patients.

Reference

Fuchs KJ, Göransson M, Kester MGD, et al. DNA barcoded peptide-MHC multimers to measure and monitor minor histocompatibility antigen-specific T cells after allogeneic stem cell transplantation. J Immunother Cancer. 2024;12(12):e009564. Published 2024 Dec 9. http://doi.org/10.1136/jitc-2024-009564