-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

901 Memory CD4+ T Cells Recognize Divergent HLA-DP Immunopeptidomes and Contribute to Leukemia Control after Allogeneic HCT

Program: Oral and Poster Abstracts
Type: Oral
Session: 701. Experimental Transplantation: Basic and Translational: GVHD, GVL and Alloimmunity
Hematology Disease Topics & Pathways:
Research, Translational Research, Diseases, Immune mechanism, Immunology, Lymphoid Malignancies, Adverse Events, Computational biology, Myeloid Malignancies, Biological Processes, Technology and Procedures, Study Population, Human, Omics technologies
Monday, December 9, 2024: 2:45 PM

Kulvara Kittisares, MD1,2*, Pietro Crivello, PhD1*, Thorben Walther1*, Maryam Mohamaddokht1,3*, Thuja Arrieta Bolaños, PhD1*, Luisa Betke, PhD1*, Dominik Lux4*, Thilo Bracht, PhD4,5*, Malte Bayer, PhD4,5*, Sarah Flossdorf6*, Effie Wang Petersdorf, MD7*, Amin T. Turki, MD1,8*, Peter Horn, MD9*, Johannes Köster, PhD10*, Astrid M. Westendorf, PhD11*, J.H. Frederik Falkenburg, MD, PhD12, Marieke Griffioen, PhD12*, Barbara Sitek, PhD4,5*, Thomas Schroeder13*, Marie Bleakley, PhD, MBBS, MMSc7, Katharina Fleischhauer, MD1,14* and Esteban Arrieta-Bolanos14,15*

1Institute for Experimental Cellular Therapy, University Hospital Essen, Essen, Germany
2Department of Transfusion Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
3Institute of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany
4Medical Proteome Center, Center for Protein Diagnostics (PRODI), Ruhr University Bochum, Bochum, Germany
5Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Germany
6Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University of Duisburg-Essen, Essen, Germany
7Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA
8Institute for AI in Medicine, University Hospital Essen, Essen, Germany
9Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
10Bioinformatics and Computational Oncology, Institute for Artificial Intelligence in Medicine (IKIM), University of Duisburg-Essen, Essen, Germany
11Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Esse, Essen, Germany
12Hematology, Leiden University Medical Center, Leiden, Netherlands
13Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
14German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Essen, Germany
15Institute for Experimental Cellular Therapy, Essen University Hospital, Essen, Germany

While naïve T cells are considered the main mediators of alloreactivity after hematopoietic cell transplantation (HCT), the role of memory T cells in these allo-immune responses and their clinical consequences is more debated. Differences between naïve and memory subsets are at the basis of clinical trials using naïve cell-depleted grafts in allogeneic HCT (Bleakley, J Clin Invest 2015 and JCO 2020). In unrelated HCT, patient and donor HLA-DP allotypes present immunopeptidomes with different degrees of divergence regulated by the peptide editor HLA-DM, which determine the strength and diversity of clinically relevant CD4+ T-cell alloresponses (Meurer, Blood 2021). In particular, HLA-DPB1 allele matches and core permissive mismatches involve immunopeptidomes with low divergence, the former composed mainly of minor histocompatibility antigen (mHAg) peptides, while non-core permissive and non-permissive mismatches present immunopeptidomes with high divergence (Arrieta-Bolaños, Blood 2022 and 2024). It is currently unknown how these immunopeptidome differences influence the alloreactive capacity of naïve vs memory CD4+ cells. Here, we hypothesized that the relative contribution of naive vs memory CD4+ T cells to alloreactivity against HLA-DP and its clinical consequences in HCT could vary according to the degree of immunopeptidome divergence between the allotypes from patient and donor. In CD137 upregulation assays, memory cell-mediated alloresponses from healthy donors were significantly weaker against HeLa cells expressing HLA-DP with low (n=48) compared to high (n=34) immunopeptidome divergence in the presence of HLA-DM (mean ± standard deviation 5.9% ± 7.6% vs 33.4 ± 22.3%, p<0.01). Mass spectrometry-based analysis of the HLA-DP immunopeptidome coupled with whole-exome sequencing of responder and target cells showed that its de-regulation by the absence of HLA-DM increased the presentation of mHAg peptides. This in turn recruited memory T cells into the alloresponse against HLA-DP with low immunopeptidome divergence (7.9 ± 9.9% vs 33.9 ± 14.6%, p<0.0001), and also significantly increased their alloreactive T-cell receptor-αβ diversity. Both naïve and memory cells produced high amounts of pro-inflammatory cytokines interferon-γ and tumor necrosis factor-α when exposed to highly divergent HLA-DP immunopeptidomes, while in this context interleukin-17 was produced exclusively by memory cells. Healthy donor alloreactive memory CD4+ T cells readily recognized and killed leukemic and non-leukemic cell lines expressing HLA-DP allotypes with high immunopeptidome divergence. In samples collected from patients one month after standard unmanipulated unrelated HCT, donor-derived peripheral blood CD4+ T cells were predominantly of memory phenotype and also showed significantly better recognition of HLA-DP with high (N=9) compared to low (N=10) immunopeptidome divergence in CD137 upregulation (4.62 ± 3.61% vs 0.82 ± 1.12%, p<0.01) and cytotoxicity assays against both HeLa and leukemic cell lines expressing the relevant patient HLA-DP allotype. In a prospective clinical trial with naïve T cell-depleted allografts (Bleakley, JCO 2022; NCT02220985, NCT01858740, NCT03970096), the probability of relapse-free survival differed among patients with HLA-DP disparities with high (n=12) compared to low (n=47) immunopeptidome divergence (p=0.02), with the 5-year probabilities of relapse-free survival being 100% versus 62%, respectively. This was correlated with a lower incidence disease relapse in highly divergent patient-donor pairs, but similarly low cumulative incidences of severe acute and chronic graft-versus-host disease regardless of HLA-DP immunopeptidome divergence. There were no statistically significant differences in overall survival. Overall, these findings support an important participation of memory CD4+ T cells in alloresponses against mismatched HLA-DP with high immunopeptidome divergence that is associated with a beneficial effect for malignant disease control after unrelated HCT. This bears implications for harnessing and exploiting memory T-cell alloreactivity in HCT and cellular therapies.

Disclosures: Turki: Janssen: Other: Travel reimbursements; Novartis: Other: Travel reimbursements; Pfizer: Consultancy; CSL Behring: Consultancy; Onkowissen.tv: Speakers Bureau; Neovii: Other: Travel reimbursements; Biomarin, AMGEN: Speakers Bureau; Maat Pharma: Consultancy.

Previous Abstract | Next Abstract >>
*signifies non-member of ASH