TY - JOUR
T1 - S100A9 upregulated by IFNGR signaling blockade functions as a novel GVHD suppressor without compromising GVL in mice
AU - Kim, Sena
AU - Lim, Sora
AU - Kim, Boram
AU - Ritchey, Julie
AU - Vij, Kiran
AU - Prior, Julie
AU - Marsala, Lynne
AU - Stoner, Alyssa
AU - Gao, Feng
AU - Achilefu, Samuel
AU - Cooper, Matthew L.
AU - DiPersio, John F.
AU - Choi, Jaebok
N1 - Funding Information:
J.C. is a Gabrielle’s Angel Foundation for Cancer Research (GAFCR) Research Fellow and supported by Amy Strelzer Manasevit Research Program which is funded through Be The Match Foundation and the National Marrow Donor Program, the Alvin J. Siteman Cancer Center through The Foundation for Barnes-Jewish Hospital and the National Institutes of Health (NIH), National Cancer Institute (NCI) (P30 CA091842; the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH). St. Baldrick’s Foundation, and Washington University SPORE in Leukemia, SPORE Diversity Program (NIH, NCI grant P50 CA171963), NIH, National Institute of Allergy and Infectious Diseases (R21 AI155990), Emerson Collective, and the Alvin J. Siteman Cancer Center through The Foundation for Barnes-Jewish Hospital. J.F.D. is supported by NIH, NCI grant R35 CA210084-01. M.L.C. is supported by Washington University Molecular Imaging Center pilot Research Project. The Washington University Molecular Imaging Center provided bioluminescence imaging and is supported by the NIH, Office of the Director grant S10 OD027042 and NIH, NCI grant P30 CA091842 (Siteman Cancer Center Small Animal Cancer Imaging shared resource).
Publisher Copyright:
© 2023 The American Society of Hematology
PY - 2023/2/23
Y1 - 2023/2/23
N2 - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for both malignant and nonmalignant hematologic disorders. However, graft-versus-host disease (GVHD) and malignant relapse limit its therapeutic success. We previously demonstrated that the blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells resulted in a reduction in GVHD while preserving graft-versus-leukemia (GVL) effects. However, the underlying molecular mechanisms remain inconclusive. In this study, we found that S100A9 is a novel GVHD suppressor upregulated when IFNGR is blocked in T cells. Both Ifngr1−/− and S100a9-overexpressing T cells significantly reduced GVHD without compromising GVL, altering donor T-cell trafficking to GVHD target organs in our mouse model of allo-HSCT. In addition, in vivo administration of recombinant murine S100A9 proteins prolongs the overall survival of recipient mice. Furthermore, in vivo administration of anti-human IFNGRα neutralizing antibody (αhGR-Nab) significantly upregulates the expression of S100A9 in human T cells and improved GVHD in our mouse model of xenogeneic human peripheral blood mononuclear cell transplantation. Consistent with S100a9-overexpressing T cells in our allo-HSCT model, αhGR-Nab reduced human T-cell trafficking to the GVHD target organs. Taken together, S100A9, a downstream molecule suppressed by IFNGR signaling, functions as a novel GVHD suppressor without compromising GVL.
AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for both malignant and nonmalignant hematologic disorders. However, graft-versus-host disease (GVHD) and malignant relapse limit its therapeutic success. We previously demonstrated that the blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells resulted in a reduction in GVHD while preserving graft-versus-leukemia (GVL) effects. However, the underlying molecular mechanisms remain inconclusive. In this study, we found that S100A9 is a novel GVHD suppressor upregulated when IFNGR is blocked in T cells. Both Ifngr1−/− and S100a9-overexpressing T cells significantly reduced GVHD without compromising GVL, altering donor T-cell trafficking to GVHD target organs in our mouse model of allo-HSCT. In addition, in vivo administration of recombinant murine S100A9 proteins prolongs the overall survival of recipient mice. Furthermore, in vivo administration of anti-human IFNGRα neutralizing antibody (αhGR-Nab) significantly upregulates the expression of S100A9 in human T cells and improved GVHD in our mouse model of xenogeneic human peripheral blood mononuclear cell transplantation. Consistent with S100a9-overexpressing T cells in our allo-HSCT model, αhGR-Nab reduced human T-cell trafficking to the GVHD target organs. Taken together, S100A9, a downstream molecule suppressed by IFNGR signaling, functions as a novel GVHD suppressor without compromising GVL.
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U2 - 10.1182/blood.2021012687
DO - 10.1182/blood.2021012687
M3 - Article
C2 - 36477272
AN - SCOPUS:85148039136
SN - 0006-4971
VL - 141
SP - 945
EP - 950
JO - Blood
JF - Blood
IS - 8
ER -