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 6

T cell–derived IFN-γ delivered in cis or in trans is required for CD4-mediated GVL.

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T cell–derived IFN-γ delivered in cis or in trans is required for CD4-me...
Irradiated B6 mice were reconstituted with BALB/c BM and B6 B2m–/– mBC-CML with no T cells or with the following BALB/c background T cells: (i) WT CD4 cells; (ii) IFN-γ–deficient CD4 cells; (iii) WT CD4 cells plus WT CD8 cells; (iv) IFN-γ–deficient CD4 cells plus WT CD8 cells; or (v) IFN-γ–deficient CD4 cells plus IFN-γ–deficient CD8 cells. Cohorts were sacrificed 10–14 days after transplantation, and mBC-CML cells were analyzed by flow cytometry. (A) Representative flow cytometry from splenocytes. (B) Percentage of leukemic splenocytes from individual mice (n = 3 independent experiments). Each symbol represents data from an individual mouse; horizontal lines indicate mean values. (C) Upper panel: WT, but not IFN-γ–deficient, CD4 or CD8 cells induced MHCII upregulation on mBC-CML LSCs. The upper panel shows LSC MHCII expression. Each line represents data from an individual mouse. Lower panel: Percentage of LSCs that were MHCII+ from 2 of 3 experiments. Each symbol represents data from an individual mouse; horizontal lines indicate the mean values. Insufficient numbers of LSCs were present to analyze in the third experiment (see bottom panel in Figure 5B). (D) In 2 of 3 experiments, the addition of WT CD8 cells, but not IFN-γ–deficient CD8 cells, to IFN-γ–deficient CD4 cells prolonged survival (data were combined from 2 experiments). P = 0.0037 comparing the KO CD4 + WT CD8 group to either the KO CD4 or KO CD4 + KO CD8 groups.