Cieri et al. set out to identify immunologically relevant genetic differences (SNPs) between stem cell transplant donors and recipients resulting in minor histocompatibility antigens (mHAgs) of clinical relevance. Using whole-exome sequencing to comprehensively search for SNPs, along with immunopeptidomics, in vitro immunogenicity, and extensive curation of expression in normal tissue databases, the researchers found a strong correlation between mHAg load and graft-vs-host disease in a well curated patient data set. Focusing on expression in leukemic and hematopoietic cells, the team identified a set of 87 mHAgs that would be useful to enhance the graft-vs-leukemia effect.
Contributed by Ed Fritsch
ABSTRACT: T cell alloreactivity against minor histocompatibility antigens (mHAgs)-polymorphic peptides resulting from donor-recipient (D-R) disparity at sites of genetic polymorphisms-is at the core of the therapeutic effect of allogeneic hematopoietic cell transplantation (allo-HCT). Despite the crucial role of mHAgs in graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD) reactions, it remains challenging to consistently link patient-specific mHAg repertoires to clinical outcomes. Here we devise an analytic framework to systematically identify mHAgs, including their detection on HLA class I ligandomes and functional verification of their immunogenicity. The method relies on the integration of polymorphism detection by whole-exome sequencing of germline DNA from D-R pairs with organ-specific transcriptional- and proteome-level expression. Application of this pipeline to 220 HLA-matched allo-HCT D-R pairs demonstrated that total and organ-specific mHAg load could independently predict the occurrence of acute GvHD and chronic pulmonary GvHD, respectively, and defined promising GvL targets, confirmed in a validation cohort of 58 D-R pairs, for the prevention or treatment of post-transplant disease recurrence.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, U
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. (4) Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. (5) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (6) Department of Immunology, Instituto de Investigacin Sanitaria Princesa (IIS-IP), Hospital Universitario de La Princesa, Madrid, Spain. (7) Department of Hematology, Instituto de Investigacin Sanitaria Princesa (IIS-IP), Hospital Universitario de La Princesa, Madrid, Spain. (8) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Harvard Medical School, Boston, MA, USA. (12) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (13) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (14) Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. (15) Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. (16) Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. Department of Proteomic and Genomic Technologies, Genentech Inc, South San Francisco, CA, USA. (17) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (18) Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. (19) Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. (20) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Hematology, Oncology, and Tumorimmunology, Campus Virchow Klinikum, Berlin, Charit-Universittsmedizin Berlin, corporate member of Freie Universitt Berlin and Humboldt-Universitt zu Berlin, Berlin, Germany. (22) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (23) Harvard Medical School, Boston, MA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. (25) Harvard Medical School, Boston, MA, USA. Division Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA. (28) Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. (29) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Computer Science, Metropolitan College, Boston University, Boston, MA, USA. Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark. (30) Department of Immunology, Instituto de Investigacin Sanitaria Princesa (IIS-IP), Hospital Universitario de La Princesa, Madrid, Spain. Department of Medicine, School of Medicine, Universidad Autnoma de Madrid, Madrid, Spain. (31) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. (32) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. (33) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. (34) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (35) Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. (36) Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. (37) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. catherine_wu@dfci.harvard.edu. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. catherine_wu@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. catherine_wu@dfci.harvard.edu. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. catherine_wu@dfci.harvard.edu.
