Chromosome Y–encoded antigens associate with acute graft-versus-host disease in sex-mismatched stem cell transplant

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a curative option for blood cancers, but the coupled effects of graft-versus-tumor and graft-versus-host disease (GVHD) limit its broader application. Outcomes improve with matching at HLAs, but other factors are required to explain residual risk of GVHD. In an effort to identify genetic associations outside the major histocompatibility complex, we conducted a genome-wide clinical outcomes study on 205 acute myeloid leukemia patients and their fully HLA-A–, HLA-B–, HLA-C–, HLA-DRB1–, and HLA-DQB1–matched (10/10) unrelated donors. HLA-DPB1 T-cell epitope permissibility mismatches were observed in less than half (45%) of acute GVHD cases, motivating a broader search for genetic factors affecting clinical outcomes. A novel bioinformatics workflow adapted from neoantigen discovery found no associations between acute GVHD and known, HLA-restricted minor histocompatibility antigens (MiHAs). These results were confirmed with microarray data from an additional 988 samples. On the other hand, Y-chromosome–encoded single-nucleotide polymorphisms in 4 genes (PCDH11Y, USP9Y, UTY, and NLGN4Y) did associate with acute GVHD in male patients with female donors. Males in this category with acute GVHD had more Y-encoded variant peptides per patient with higher predicted HLA-binding affinity than males without GVHD who matched X-paralogous alleles in their female donors. Methods and results described here have an immediate impact for allo-HCT, warranting further development and larger genomic studies where MiHAs are clinically relevant, including cancer immunotherapy, solid organ transplant, and pregnancy.

Can Graft vs. Leukemia Effect Be Uncoupled From Graft vs. Host Disease? An Examination of Proportions

“…The SNPs when compared to the mutations used to estimate TSA, are much larger in number, indicating that mHA may provide the dominant antigen background in terms of generating alloreactivity following HCT. Similar data regarding the extent of genomic variation between transplant donors and recipients have been reported by other groups investigating genomic variation in transplant recipients, in both solid organ transplants (48) and in HCT (49)(50)(51)(52)(53), as well as in models predicting GVL specific libraries (54). This abundance of SNPs across the exome in unique HCT donor-recipient pairs is an eye-opening finding compared to the average 10 mutations per hematologic neoplasm.…”

Computational Analysis of HLA-presentation of Non-synonymous Recipient Mismatches Indicates Effect on the Risk of Chronic Graft-vs.-Host Disease After Allogeneic HSCT

“…Thus, the used covariates were: the sum of cohort frequencies of unique HLA types present in each recipient, the number of unique HLA types in each recipient, and the total number of mismatched peptides in each recipient. Furthermore, transplantation year, donor age and transplant direction (female-to-male vs. others) and the extent of matching over six HLA genes (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) for each HSCT pair were also included as covariates as these can be relevant for allo-HSCT outcome (22, 39). Each numerical predictor variable was centered and scaled.…”

“…Further, in an alternative approach, computational prediction of HLA binding affinities of amino-acid altering genetic differences has shown a difference between related and unrelated allo-HSCTs (16), and has been reported to associate with GvHD risk (17). Studies analyzing the presence of known mismatched mHAs in allo-HSCT recipients have likewise identified small effects on GvHD risk and relapse-free survival (18–22). Given the various methodological approaches and that few of these associations remain statistically significant after multiple testing adjustment, further studies are warranted to investigate the graft alloimmunity capacity.…”

Lysine demethylases KDM6A and UTY: The X and Y of histone demethylation

“…This may be attributed to mismatching for minor histocompatibility antigens [124]. There are several of these that originate from the Y chromosome, including sequences within the UTY gene [125,126]. Male recipients of HLA-identical female hematopoietic stem cell transplants were more likely to suffer graft versus host disease than male to male transplants, and his was exacerbated if there was a mismatch of the variant UTY peptide sequence with the paralogous sites of the donor's KDM6A sequences.…”

“…Male recipients of HLA-identical female hematopoietic stem cell transplants were more likely to suffer graft versus host disease than male to male transplants, and his was exacerbated if there was a mismatch of the variant UTY peptide sequence with the paralogous sites of the donor's KDM6A sequences. Graft versus host disease was not seen where the recipient UTY and donor KDM6A peptides were the same, suggesting that the donor immune system can see UTY as self if it matches its KDM6A [126]. Cytotoxic lymphocytes (CTL) from a female patient with aplastic anemia who rejected an HLA-identical stem cell transplant from a male donor were reactive to an epitope at the N terminal end of UTY preceding the TPR domains [127].…”