Identification of Minor Histocompatibility Antigens Based on the 1000 Genomes Project for Application in Therapeutic Dendritic Cell Vaccination

Minor histocompatibility antigens (mHags) are highly immunogenic, HLA-bound polymorphic peptides playing prominent roles in the development of the graft vs host disease (GvHD) as well as the therapeutic graft vs tumor (GvT) effect of allogeneic stem cell transplantation (allo-SCT). To date, a small subset of mHags has been identified as genuinely hematopoietic system-specific. This small number of conceptually GvT-associated mHags are currently being tested in various clinical trials for the feasibility and efficacy of inducing an exclusive GvT effect without GvHD in patients with relapsing haematological malignancies after allo-SCT. Nonetheless, a broader and timely application of mHags as therapeutic tools in allo-SCT, as well as the development of appropriate GvHD prevention strategies still requires more insights that can be acquired through the identification of a much larger set of mHags presented by various HLA molecules in different ethnic populations. Recently, the introduction of genome-wide association (GWAS)-based strategies, despite a number of drawbacks, significantly accelerated the identification of mHags. To develop a strategy that can overcome the drawbacks of these earlier developed strategies, we now integrated our previously developed GWAS methodology [1,2] with the comprehensive genomic databases from the 1000 Genomes Project [3]. We show that the data set of the 1000 Genomes Project is suitable to identify all theoretical possible mHags, hereby enabling us to delineate important yet unknown characteristics of mHags. Furthermore, we demonstrate the actual power of this novel approach by the rapid and unambiguous identification of the HLA-DP4 restricted mHag UTDP4-1, which -despite extensive efforts in the past 15 years- could not be identified using any of the previously developed biochemical, molecular biological or genetic strategies. The 1000 Genomes Project-based identification of mHags thus represents a very rapid, convenient and robust method for the identification of new mHags, that will not only improve the understanding of the yet unknown facets of mHags but may also significantly enlarge the arsenal of targets for immunotherapy in haematological cancers.

1. Spaapen et al., J.Exp.Med. 2008 Nov 24;205(12):2863-72.

2. Oostvogels et al., Leukemia 2013 Mar;27(3):642-9.

3. Abecasis et al., Nature 2012 Nov 1;491(7422):56-65.