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Allogeneic stem cell transplantation (allo-SCT) can induce remission in patients with hematological malignancies due to graft-versus-tumor (GVT) responses. This immune-mediated anti-tumor effect, however, is often accompanied by detrimental graft-versus-host disease (GVHD). Both GVT and GVHD are mediated by minor histocompatibility antigen (MiHA)-specific T cells recognizing peptide products from polymorphic genes that differ between recipient and donor. In this study, we evaluated whether mismatches in a panel of seventeen MiHA are associated with clinical outcome after partial T cell-depleted allo-SCT. Comprehensive statistical analysis revealed that DNA mismatches for one or more autosomal-encoded MiHA was associated with increased relapse-free survival in sibling transplants, (P =0.04), particularly in patients suffering from multiple myeloma (P =0.02). Moreover, mismatches for the ubiquitous Y chromosome-derived MiHA resulted in a higher incidence of acute GVHD (grade 3–4; P =0.004), while autosomal MiHA mismatches, ubiquitous or restricted to hematopoietic cells, were not associated with severe GVHD. Finally, we demonstrated considerable differences between MiHA in their capability to induce in vivo T cell responses using dual-color tetramer analysis of peripheral blood samples collected post-SCT. Importantly, detection of MiHA-specific T cell responses was associated with improved relapse-free survival in sibling transplants (P =0.01). Our findings provide a rationale to further boost GVT immunity towards autosomal MiHA with a hematopoietic restriction to improve outcome after HLA-matched allo-SCT.

Highlights Activation of NF-κB signaling in mesenchymal cells is common in LR-MDS.Activation of NF-κB in mesenchymal cells leads to transcriptional overexpression of inflammatory factors including negative regulators of hematopoiesis.Activation of NF-κB attenuates HSPC numbers and function ex vivo.

4136 Purpose: Allogeneic stem cell transplantation (allo-SCT) can induce remission in patients with hematological malignancies due to graft-versus-tumor (GVT) responses. This, however, is often accompanied by graft-versus-host disease (GVHD). Both the GVT effect and GVHD are mediated by minor histocompatibility antigen (MiHA)-specific T cells recognizing peptide products from polymorphic genes that differ between recipient and donor. Here, we evaluated whether MiHA mismatches are associated with clinical outcome after partial T cell depleted allo-SCT. Patients and Methods: We retrospectively analyzed the impact of MiHA mismatches in a cohort of 327 patients who received a partially T cell-depleted allo-SCT because of a hematological malignancy. MiHA allele genotyping was performed by fluorescence-based competitive allele-specific PCR. Subsequently, a multivariable statistical analysis of immunogenic MiHA disparity rates and association with clinical outcome was performed. In addition, development of MiHA-specific T cell responses was assessed by dual-color tetramer staining. Results: Statistical analysis revealed that an autosomal MiHA disparity on DNA level associates with increased relapse-free survival in sibling transplants, especially in patients transplanted for multiple myeloma. In addition, mismatches for the ubiquitous Y chromosome-encoded MiHA resulted in more acute GVHD (grade 3–4), while other MiHA mismatches, either ubiquitous or restricted to hematopoietic cells, were not associated with GVHD. Finally, we demonstrated considerable differences between MiHA in the capability to induce in vivo T cell responses post-transplantation. Conclusion: These data support that autosomal MiHA contribute to the induction of GVT immunity providing a rationale for MiHA-based post-transplantation immunotherapy to prevent and treat persistent and recurrent cancer following allo-SCT. Disclosures: No relevant conflicts of interest to declare.