Effect of SIRPalpha mismatch on the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA matched related donor

PROJECT SUMMARY/ABSTRACT Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for patients with hematologic malignancies. It is believed that alloreactivity upon HSCT is initiated by lymphoid cells that express rearranging receptors upon recognizing the alloantigens on the graft. Unlike lymphoid cells, cells from the innate immune system do not express rearranging receptors and are nonspecifically induced by “danger” molecules. However, recent studies demonstrated that the innate immune system could specifically distinguish the non-self graft and subsequently enhance the alloimmune response. Signal regulatory protein α (SIRPα) is a polymorphic immunoglobulin receptor that is exclusively expressed on the surface of innate cells. The interaction between SIRPα and its ubiquitously expressed ligand, CD47, suppresses the macrophage's phagocytic function. As shown in the murine transplant model, mismatches of SIRPα between donor and recipients can upregulate the allorecognition response. Our group recently investigated the role of SIRPα variant mismatch in recipients of allo-HSCT from a human leukocyte antigen (HLA)-matched related donors (MRD) for the treatment of different hematological malignancies. We found that for the first time, donor/recipient SIRPα mismatch is commonly detected and associated with a significantly increased risk of chronic graft-versus-host disease (cGVHD) and a lower rate of early relapse (Blood Advances 2021; Frontier in Immunology 2022). We proposed a large registry-based study to validate our results in allo-HSCT recipients with MRD, which is one of the most common donor sources in allo-HSCT. The study is approved by the Center for International Blood and Marrow Transplant Research (CIBMTR) immunobiology working committee. CIBMTR and the National Marrow Donor Program (NMDP) will facilitate the study by providing scientific and statistical expertise, as well as associated clinical outcome information and biospecimens. We hypothesize that the mismatched SIRPα elicits a non-self recognition which will further promote adaptive immunity leading to a higher risk of cGVHD and a lower risk of relapse. In Aim 1, we will perform a retrospective analysis of the SIRPα mismatch in allo-HSCT with MRD using the CIBMTR data and specimens. Aim 2 is to determine the relative clinical significance of SIRPα mismatch in the entire cohort and the subgroups of allo-HSCT. The study will not only define the clinical role of SIRPα variant mismatch in the allo-HSCT setting but also significantly advance our knowledge of GVHD/ Graft versus Leukemia (GVL) and the allorecognition of the innate immune system in the context of stem cell transplant.