Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) can be a curative treatment for hematological diseases. After HLA-matched alloHSCT, donor T cells may recognize minor histocompatibility antigens (MiHAs), which are polymorphic HLA-binding peptides on patient cells that are absent from donor cells due to genetic differences. Donor T cells can induce beneficial anti-tumor effects if MiHAs are targeted on malignant hematopoietic cells in the patient, while graft-versus-host disease (GvHD) may develop if MiHAs are targeted on patients’ healthy non-hematopoietic tissues. Methods We previously isolated T-cell clones from patients responding to donor lymphocyte infusions (DLIs) after HLA-matched alloHSCT, and identified HLA class I-restricted MiHAs. To investigate MiHA-specific T-cell responses in patients, we here sequenced the T-cell receptors (TCRs) of MiHA-specific T-cell clones and identified 394 distinct TCRs against 122 MiHAs. We used the collection of identified TCRs to measure frequencies of matched MiHA-specific TCRs in 39 patients responding to DLI with antitumor responses accompanied with no (n=9), limited (n=8) or severe (n=22) GvHD. Results The data showed higher MiHA-specific TCR frequencies in patients with severe GvHD, which were mainly driven by clonal expansion. Moreover, within the diverse MiHA-specific TCR repertoires in these patients, we identified five public TCRs against four MiHAs with identical CDR3 regions and several TCRs targeting MiHAs with similar, but not identical, CDR3 regions. Conclusion Patients with severe GvHD have high MiHA-TCR frequencies mainly driven by clonal expansion, and that MiHA-specific TCR repertoires in patients responding to DLI after alloHSCT are highly diverse with a few public clonotypes.
K. Fuchs, M. van de Meent, M. Kester et al.· Journal for ImmunoTherapy of...· 0 citations
The immunosuppressive bone marrow microenvironment is an important contributor to the limited success of immunotherapy in acute myeloid leukemia (AML), but the cellular interactions underlying AML immune evasion are incompletely understood. We therefore generated a single-cell spatial transcriptomic and proteomic atlas using 148 bone biopsies from 113 individuals comprising pediatric and adult AML at diagnosis and non-leukemic controls. We observed an expansion of regulatory T cells (Tregs) in AML, with stronger colocalization between Tregs and macrophages compared to non-leukemic bone marrow. Distinct cellular neighborhoods were enriched for myeloid progenitor-like cells together with macrophages and T cells, which correlated with higher macrophage and T cell immune checkpoint expression. Moreover, these neighborhoods were associated with specific AML subtypes, especially KMT2A-rearranged and RUNX1::RUNX1T1 AML. These spatial patterns were validated by identification of malignant cells via in situ fusion detection in RUNX1::RUNX1T1 cases. Functional experiments revealed that macrophages and AML cells not only actively recruit Tregs, but also promote naïve T cell differentiation into Tregs. Spatially informed ligand-receptor analysis predicted the involvement of the Galectin-9 – CD44/TIM-3 axis in this immunosuppressive crosstalk, which was supported by in vitro inhibition of CD44 and/or TIM-3 preventing macrophage- and AML-induced Treg differentiation. Collectively, this comprehensive spatial map of the AML bone marrow identified tripartite crosstalk between AML, macrophages, and T cells mediated by the Galectin-9 – CD44/TIM-3 axis as a key component of the immunosuppressive microenvironment. Targeting Galectin-9 – CD44/TIM-3 interactions may be a promising strategy to overcome immune evasion and enhance immunotherapeutic success in AML. Highlights Spatial transcriptomic and proteomic atlas of pediatric and adult acute myeloid leukemia (AML) bone marrow Increased colocalization of macrophages and regulatory T cells (Tregs) in AML Macrophages and AML cells induce differentiation of naïve T cells to Tregs in vitro, which can be prevented by inhibition of CD44 or TIM-3
M. van der Meulen, Emma S. Pool, A. Perzolli et al.· bioRxiv· 0 citations
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