Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity
Catherine Matte-Martone, … , John T. Harty, Warren D. Shlomchik
Catherine Matte-Martone, … , John T. Harty, Warren D. Shlomchik
Published June 12, 2017
Citation Information: J Clin Invest. 2017;127(7):2765-2776. https://doi.org/10.1172/JCI85736.
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Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity

Abstract

The graft-versus-leukemia (GVL) effect in allogeneic hematopoietic stem cell transplantation (alloSCT) is potent against chronic phase chronic myelogenous leukemia (CP-CML), but blast crisis CML (BC-CML) and acute myeloid leukemias (AML) are GVL resistant. To understand GVL resistance, we studied GVL against mouse models of CP-CML, BC-CML, and AML generated by the transduction of mouse BM with fusion cDNAs derived from human leukemias. Prior work has shown that CD4+ T cell–mediated GVL against CP-CML and BC-CML required intact leukemia MHCII; however, stem cells from both leukemias were MHCII negative. Here, we show that CP-CML, BC-CML, and AML stem cells upregulate MHCII in alloSCT recipients. Using gene-deficient leukemias, we determined that BC-CML and AML MHC upregulation required IFN-γ stimulation, whereas CP-CML MHC upregulation was independent of both the IFN-γ receptor (IFN-γR) and the IFN-α/β receptor IFNAR1. Importantly, IFN-γR–deficient BC-CML and AML were completely resistant to CD4- and CD8-mediated GVL, whereas IFN-γR/IFNAR1 double-deficient CP-CML was fully GVL sensitive. Mouse AML and BC-CML stem cells were MHCI+ without IFN-γ stimulation, suggesting that IFN-γ sensitizes these leukemias to T cell killing by mechanisms other than MHC upregulation. Our studies identify the requirement of IFN-γ stimulation as a mechanism for BC-CML and AML GVL resistance, whereas independence from IFN-γ renders CP-CML more GVL sensitive, even with a lower-level alloimmune response.

Authors

Catherine Matte-Martone, Jinling Liu, Meng Zhou, Maria Chikina, Douglas R. Green, John T. Harty, Warren D. Shlomchik

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Figure 3

IFN-γ stimulation is required for TMH60-mediated GVL against H60+ mBC-CML and CD4- and CD8-mediated GVL against MLL-AF9–induced AML.

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IFN-γ stimulation is required for TMH60-mediated GVL against H60+ mBC-CM...
(A–E). Irradiated B6.H60 mice were reconstituted with C3H.SW BM, WT or Ifngr–/– B6.H60 mBC-CML, with no T cells or with and 5 × 104 sort-purified CD8+CD44+ cells from H60-vaccinated donors, which contained 3,500 TetH60+ cells. (A) Post-transplantation survival. (B) Representative TetH60 staining of blood CD8 cells from WT and Ifngr–/– H60+ mBC-CML recipients and their quantitation (C) on day 14 after transplantation. The percentage of blood NGFR+EGFP+ cells on day 14 after transplantation and the percentage of these cells that were MHCII+ are shown in D and E, respectively. For C–E, each symbol represents data from an individual mouse; horizontal lines represent the mean. P = 0.0034, comparing survival of recipients of WT H60+ BC-CML, with or without TMH60. P = 0.378, comparing survival of recipients of Ifngr–/– H60+ mBC-CM with or without TMH60. (F–H) Irradiated B6 mice were reconstituted with C3H.SW BM, WT or Ifngr–/– MLL-AF9 AML with no T cells, or with C3H.SW CD4 or CD8 cells. Spleen and BM cells were harvested on day 13 after transplantation and analyzed for MLL-AF9 AML (GFP+) MHCII expression (F). Survival for CD4-mediated and CD8-mediated GVL is shown in G and H, respectively. P ≤ 0.0016, comparing the survival in the WT mAML BM-alone group with WT CD4 or CD8 recipients; P = 0.024, comparing Ifngr–/– BM alone with CD4 recipients; P = 0.0079 and P = 0.0053, comparing CD4 and CD8 recipients of WT versus Ifngr–/– MLL-AF9 AML, respectively. P values determined by 2-tailed Mann-Whitney U test. Data in G and H were combined from 2 repetitions.