Among 494 patients with myeloid neoplasms treated with HSCT, patients with high class-II HLA evolutionary divergence (HED, an indirect measure of epitope diversity) had a lower rate of relapse and better overall survival than those with low class-II HED. High class-I and -II HED was also associated with an increased number, but low clonal expansion of cancer-related clonotypes. In post-transplant relapses (but not relapse directly following chemotherapy), HLA-I and -II genes were preferentially targeted by somatic mutations, or expression was downregulated, suggesting HLA mutation and dysregulation as mechanisms of immune escape.
Contributed by Lauren Hitchings
ABSTRACT: Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experience relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune reactions and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.
Author Info: (1) Department of Clinical Hematology, CHRU de Nancy Brabois. (2) Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Clevelan
Author Info: (1) Department of Clinical Hematology, CHRU de Nancy Brabois. (2) Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. (3) Novocraft Technologies Sdn Bhd, Kuala Lumpur, Malaysia. (4) Inserm UMR S1256 Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, 54500 Nancy, France. (5) Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, NC, USA. (6) Histocompatibility department, CHRU Nancy, Nancy, France. (7) Department of Clinical Hematology, CHRU Nancy, Nancy, France. (8) Histocompatibility department, CHRU Nancy, Nancy, France. (9) Department of Clinical Hematology, CHRU Nancy, Nancy, France. (10) Department of Clinical Hematology, CHRU Nancy, Nancy, France. (11) Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. (12) Leukemia program, Hematology Department, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. (13) Blood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. (14) Blood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. (15) Sarah Cannon Transplant and Cellular Therapy Network, Nashville, TN, USA. (16) Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. (17) Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
