New research out of Dana-Farber, the Broad, and Harvard Medical School improves our ability to forecast the alloreactivity of hematopoietic cell transplants (HCTs), which could lead to fewer post-transplant diseases. Researchers could predict alloreactivity using a multi-omic approach to identify mHAgs, polymorphic peptides that can cause immune responses between donors and transplant recipients, even if they are HLA-matched. The study, published in Nature Biotechnology, could significantly improve patient outcomes in precision immuno-oncology and allogeneic HCT (allo-HCT).
The cause of allo-HCT-related disease
The leading cause of alloreactivity in HCT is the immune system’s reaction to mHAgs. In the same way that tumor neoantigens are recognized as foreign by donor T cells, mHAgs lack central tolerance, making them highly immunogenic. In contrast to tumor-specific antigens, mHAgs manifest not as somatic events but as germline traits encoded by polymorphic genes.
There are two sides to the alloreactive coin when it comes to allo-HCT. On the one hand, the most detrimental immune-related complication following allo-HCT, graft-versus-host disease (GvHD), can be attributed to a donor-derived immune response directed against mHAgs. This response may be broadly expressed across tissues or specifically in GvHD-affected tissues. On the other hand, the curative graft-versus-leukemia (GvL) effect can be conceptualized as the result of productive donor immune responses against mHAgs expressed on hematopoietic cells, including but not limited to epitopes with hematopoietic tissue restriction.
Personalizing mHAg prediction in allo-HCT
In the present study, researchers developed a comprehensive analytic framework to predict candidate mHAgs expressed in organs that are frequently targeted by GvHD or in hematopoietic cells. Using this pipeline on a group of 220 HLA-matched donor-recipient pairs, they found links with GvHD outcomes and identified possible GvL targets for preventing or treating disease recurrence after transplant.
For GvHD risk, the molecular characterization of donor-recipient pairs can facilitate the design of personalized post-HCT treatments to minimize this highly morbid condition. This includes incorporating additional immunosuppressive therapies introduced early for high-risk patients or reduced-intensity approaches in low-risk settings. For GvL, the analysis paves the way for generating ‘off-the-shelf’ GvL mHAg-targeting vaccines or adoptive T cell therapeutics.
Additionally, the researchers found two pathways that connect organ-specific mHAg expression to various GvHD risk factors. In the case of lung chronic GvHD, the clinical outcome was associated with the burden of lung-specific mHAgs. Alternatively, a few particular immunodominant liver mHAgs were responsible for the clinical symptoms in liver acute GvHD. Potential driver mHAgs specific to organs beyond liver and lung GvHD could be better identified with further research involving larger cohorts.
Future studies can use this pipeline’s capacity to effectively process massive patient datasets to hone the algorithm for more sensitive prognostication and HCT response prediction. Allo-HCT study populations from various ethnic backgrounds, especially those from Asia or Africa, could be analyzed as part of these datasets. This would increase the number of usable GvL mHAgs and population coverage.
