Associations of minor histocompatibility antigens with outcomes following allogeneic hematopoietic cell transplantation

Jadi, Othmane; Tang, Hancong; Olsen, Kelly; Vensko, Steven; Zhu, Qianqian; Wang, Yiwen; Haiman, Christopher A.; Pooler, Loreall; Sheng, Xin; Brock, Guy; Webb, Amy; Pasquini, Marcelo C.; McCarthy, Philip L.; Spellman, Stephen R.; Hahn, Theresa; Vincent, Benjamin G.; Armistead, Paul M.; Sucheston‐Campbell, Lara E.

doi:10.1002/ajh.26925

Cited by 3 publications

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“…This concise library of MiHAs allows quantification of MiHA-specific T cells in large patient cohorts to understand the relevance of MiHAs for clinical outcome after alloSCT. Previous studies investigated SNP mismatches 82 or predicted HLA-binding polymorphic peptides, 83 , 84 , 85 but failed to find clear associations with GVHD or GVL. These studies, however, were performed without verification whether the peptides are presented on the cell or able to evoke an immune response.…”

Section: Discussionmentioning

confidence: 95%

Expanding the repertoire reveals recurrent, cryptic, and hematopoietic HLA class I minor histocompatibility antigens

Fuchs,

van de Meent,

Honders

et al. 2024

Blood

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Allogeneic stem cell transplantation (alloSCT) is a curative treatment for hematological malignancies. After HLA-matched alloSCT, anti-tumor immunity is caused by donor T cells recognizing polymorphic peptides, designated minor histocompatibility antigens (MiHAs), that are presented by HLA on malignant patient cells. However, T cells often target MiHAs on healthy non-hematopoietic tissues of patients, thereby inducing side effects known as Graft-versus-Host Disease. Here, we aimed to identify the dominant repertoire of HLA-I-restricted MiHAs to enable strategies to predict, monitor or modulate immune responses after alloSCT. To systematically identify novel MiHAs by genome-wide association screening, T-cell clones were isolated from 39 transplanted patients and tested for reactivity against 191 EBV-B cell lines of the 1000 Genomes Project. By discovering 81 new MiHAs, we more than doubled the antigen repertoire to 159 MiHAs and demonstrated that, despite many genetic differences between patients and donors, often the same MiHAs are targeted in multiple patients. Furthermore, we showed that one quarter of the antigens are cryptic, i.e. translated from unconventional open reading frames, for example long non-coding RNAs, showing that these antigen types are relevant targets in natural immune responses. Finally, using single cell RNA-seq data, we analyzed tissue expression of MiHA-encoding genes to explore their potential role in clinical outcome, and characterized 11 new hematopoietic-restricted MiHAs as potential targets for immunotherapy. In conclusion, we expanded the repertoire of HLA-I-restricted MiHAs and identified recurrent, cryptic and hematopoietic-restricted antigens, which are fundamental to predict, follow or manipulate immune responses to improve clinical outcome after alloSCT.

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