Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is routinely used to treat hematopoietic malignancies. The eradication of residual tumor cells during engraftment is mediated by donor cytotoxic T lymphocytes reactive to alloantigens. In a HLA-matched transplantation context, alloantigens are encoded by various polymorphic genes situated outside the HLA locus, also called minor histocompatibility antigens (MiHAs). Recently, MiHAs have been recognized as promising targets for post-transplantation T-cell immunotherapy as they have several appealing advantages over tumor-associated antigens (TAAs) and neoantigens, i.e., they are more abundant than TAAs, which potentially facilitates multiple targeting; and unlike neoantigens, they are encoded by germline polymorphisms, some of which are common and thus, suitable for off-the-shelf therapy. The genetic sources of MiHAs are nonsynonymous polymorphisms that cause differences between the recipient and donor proteomes and subsequently, the immunopeptidomes. Systematic description of the alloantigen landscape in HLA-matched transplantation is still lacking as previous studies focused only on a few immunogenic and common MiHAs. Here, we perform a thorough in silico analysis of the public genomic data to classify genetic polymorphisms that lead to MiHA formation and estimate the number of potentially available MiHA mismatches. Our findings suggest that a donor/recipient pair is expected to have at least several dozen mismatched strong MHC-binding SNP-associated peptides per HLA allele (116 ± 26 and 65 ± 15 for non-related pairs and siblings respectively in European populations as predicted by two independent algorithms). Over 70% of them are encoded by relatively frequent polymorphisms (minor allele frequency > 0.1) and thus, may be targetable by off-the-shelf therapeutics. We showed that the most appealing targets (probability of mismatch over 20%) reside in the asymmetric allele frequency region, which spans from 0.15 to 0.47 and corresponds to an order of several hundred (213 ± 47) possible targets per HLA allele that can be considered for immunogenicity validation. Overall, these findings demonstrate the significant potential of MiHAs as targets for T-cell immunotherapy and emphasize the need for the systematic discovery of novel MiHAs.
Highlights
T-cell immunotherapy is extremely promising in cancer treatment, as was demonstrated in a number of successful cases of targeting tumor-associated antigens (TAAs) and/or neoantigens in melanoma and other solid cancers [1]
We further focused on the nature and number of the peptides that were unique to the recipient
Most of the peptides presented in the MHC I are 9 amino acids long [35]
Summary
T-cell immunotherapy is extremely promising in cancer treatment, as was demonstrated in a number of successful cases of targeting tumor-associated antigens (TAAs) and/or neoantigens in melanoma and other solid cancers [1]. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) provides healthy blood cells, T-cell-replete graft and/ or subsequent donor lymphocyte infusions facilitate the elimination of residual disease by targeting alloantigens in the “graft versus leukemia” (GvL) reaction [2, 3]. Out of the 70 MiHAs discovered so far [11] very few are specific to the hematopoietic tissue (for review see Bleakley and Riddell [5]). It is unclear how many MiHAs remain to be discovered
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