Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation

Nicoletta Cieri^{1

2

3}, Nidhi Hookeri^{1

2

4}, Kari Stromhaug^{1

2}, Liang Li², Julia Keating⁴, Paula Díaz-Fernández⁵, Valle Gómez-García de Soria⁶, Jonathan Stevens⁷, Raphael Kfuri-Rubens^{1

2}, Yiren Shao^{1

2

4}, Kameron A Kooshesh³, Kaila Powell¹, Helen Ji¹, Gabrielle M Hernandez², Jennifer Abelin², Susan Klaeger^{2

8}, Cleo Forman^{1

4}, Karl R Clauser², Siranush Sarkizova², David A Braun^{1

2

3

9

10}, Livius Penter^{1

2

3

11}, Haesook T Kim⁴, William J Lane^{3

7}, Giacomo Oliveira^{1

2

3}, Leslie S Kean^{3

12}, Shuqiang Li^{1

13}, Kenneth J Livak^{1

13}, Steven A Carr², Derin B Keskin^{1

2

3

13

14

15}, Cecilia Muñoz-Calleja^{5

16}, Vincent T Ho^{1

3

9}, Jerome Ritz^{1

3

9}, Robert J Soiffer^{1

3

9}, Donna Neuberg⁴, Chip Stewart², Gad Getz^{2

3

17

18}, Catherine J Wu^{19

20

21

22}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
³ Harvard Medical School, Boston, MA, USA.
⁴ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Department of Immunology, Instituto de Investigación Sanitaria Princesa (IIS-IP), Hospital Universitario de La Princesa, Madrid, Spain.
⁶ Department of Hematology, Instituto de Investigación Sanitaria Princesa (IIS-IP), Hospital Universitario de La Princesa, Madrid, Spain.
⁷ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁸ Department of Proteomic and Genomic Technologies, Genentech Inc, South San Francisco, CA, USA.
⁹ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
¹¹ Department of Hematology, Oncology, and Tumorimmunology, Campus Virchow Klinikum, Berlin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
¹² Division Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
¹³ Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁴ Department of Computer Science, Metropolitan College, Boston University, Boston, MA, USA.
¹⁵ Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark.
¹⁶ Department of Medicine, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
¹⁷ Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
¹⁸ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
¹⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. catherine_wu@dfci.harvard.edu.
²⁰ Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. catherine_wu@dfci.harvard.edu.
²¹ Harvard Medical School, Boston, MA, USA. catherine_wu@dfci.harvard.edu.
²² Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. catherine_wu@dfci.harvard.edu.

PMID: 39169264
PMCID: PMC11912513 (available on 2026-06-01)
DOI: 10.1038/s41587-024-02348-3

Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation

Nicoletta Cieri et al. Nat Biotechnol. 2025 Jun.

. 2025 Jun;43(6):971-982.

doi: 10.1038/s41587-024-02348-3. Epub 2024 Aug 21.

Authors

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
³ Harvard Medical School, Boston, MA, USA.
⁴ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵ Department of Immunology, Instituto de Investigación Sanitaria Princesa (IIS-IP), Hospital Universitario de La Princesa, Madrid, Spain.
⁶ Department of Hematology, Instituto de Investigación Sanitaria Princesa (IIS-IP), Hospital Universitario de La Princesa, Madrid, Spain.
⁷ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁸ Department of Proteomic and Genomic Technologies, Genentech Inc, South San Francisco, CA, USA.
⁹ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
¹¹ Department of Hematology, Oncology, and Tumorimmunology, Campus Virchow Klinikum, Berlin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
¹² Division Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
¹³ Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁴ Department of Computer Science, Metropolitan College, Boston University, Boston, MA, USA.
¹⁵ Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark.
¹⁶ Department of Medicine, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
¹⁷ Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
¹⁸ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
¹⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. catherine_wu@dfci.harvard.edu.
²⁰ Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. catherine_wu@dfci.harvard.edu.
²¹ Harvard Medical School, Boston, MA, USA. catherine_wu@dfci.harvard.edu.
²² Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. catherine_wu@dfci.harvard.edu.

PMID: 39169264
PMCID: PMC11912513 (available on 2026-06-01)
DOI: 10.1038/s41587-024-02348-3

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.

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Conflict of interest statement

Competing interests: C.J.W. holds equity in BioNTech and receives research support from Pharmacyclics. D.B.K is a scientific advisor for Immunitrack and Breakbio and owns equity in Affimed N.V., Agenus, Armata Pharmaceuticals, Breakbio, BioMarin Pharmaceutical, Celldex Therapeutics, Editas Medicine, Gilead Sciences, Immunitybio, IMV, Lexicon Pharmaceuticals and Neoleukin Therapeutics. BeiGene supported unrelated SARS-COV-2 research at Translational Immunogenomics Lab. R.J.S. consults or is on the advisory board of Kiadis, Juno Therapeutics, Gilead, Jasper, Jazz Pharmaceuticals, Precision Biosciences, Rheo Therapeutics, Takeda and NMDP—Be the Match. J.R. receives research funding from Kite/Gilead, Novartis and Oncternal and consults or is on advisory boards for Clade Therapeutics, Garuda Therapeutics, LifeVault Bio, Smart Immune and TriArm Bio. V.T.H. receives funding from Jazz Pharmaceuticals and consults or is on advisory boards for Jazz Pharmaceuticals, Janssen, Alexion Pharmaceuticals and Omeros. W.J.L. consults or is on the advisory board of CareDx, One Lambda and Thermo Fisher Scientific and receives royalty payments from Thermo Fisher Scientific. K.J.L. holds equity in Standard BioTools and is on the scientific advisory board for MBQ Pharma. S.A.C. is a member of the scientific advisory boards of PTM BioLabs, Kymera, Seer and PrognomIQ and holds equity in the latter three. D.A.B. reports honoraria from LM Education/Exchange Services; advisory board fees from Exelixis and AVEO; personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, AbbVie, DLA Piper and Elephas; equity in CurIOS Therapeutics, Elephas and Fortress Biotech (subsidiary); research support from Exelixis (US) and AstraZeneca (UK), outside of the submitted work. G.O. is a consultant for Bicycle Therapeutics. L.S.K. is on the scientific advisory board for Mammoth Biosciences and HiFiBio; received research funding from Magenta Therapeutics, Tessera Therapeutics, Novartis, EMD Serono, Gilead Pharmaceuticals and Regeneron Pharmaceuticals; consulting fees from Vertex; grants/personal fees from Bristol Myers Squibb and royalties/partial funding for the current study from Bristol Myers Squibb. L.S.K.’s conflict of interest with Bristol Myers Squibb is managed under an agreement with Harvard Medical School. D.N. holds equity in Madrigal Pharmaceutics. G.G. receives research funds from Pharmacyclics, Ultima Genomics and IBM. G.G. receives research funds from Pharmacyclics, Bayer, Genentech, Ultima Genomics and IBM; is an inventor of patent applications related to MSMuTect, MSMutSig, MSIDetect, POLYSOLVER, SignatureAnalyzer-GPU and MinimuMM-seq; is a founder and consultant and holds privately held equity in Scorpion Therapeutics and is a founder and holds privately held equity in PreDICTA Biosciences. The other authors declare no competing interests.

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Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation

Affiliations

Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation

Authors

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Abstract

Conflict of interest statement

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Methods-only references

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