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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Research Article Immunology

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 2

The IFN-γR on mBC-CML cells is required for GVH-induced MHC upregulation and effective CD4- and CD8-mediated GVL, whereas MHCII upregulation on mCP-CML cells and GVL are independent of both the IFN-γR and IFNAR1 and STAT1/STAT2.

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The IFN-γR on mBC-CML cells is required for GVH-induced MHC upregulation...
(A) Irradiated B6 mice were reconstituted with C3H.SW BM and B6 Ifngr–/–, B6 Ifnar1–/–, or control WT B6 mBC-CML cells, with no C3H.SW T cells or C3H.SW CD4 or CD8 cells. MHCI and MHCII upregulation did not occur on Ifngr–/– mBC-CML LSCs but was intact on Ifnar1–/– LSCs. (B) Mice were transplanted as in A, except with B6 WT or Ifngr–/– mCP-CML cells. MHCII upregulation was similar in WT and gene-deficient mCP-CML LSCs. Consistent with the upregulation data, IFN-γR mBC-CML was resistant to CD4- and CD8-mediated GVL in the C3H.SW→B6 model (C) and to CD8-mediated GVL in the BALB/c→B6 model (D). In contrast, Ifngr–/– mCP-CML (E), Ifnar1–/– mBC-CML (F), Ifngr–/– Ifnar1–/– (double-KO [DKO]) mCP-CML (G), and Stat1–/– Stat2–/– mCP-CML (H) cells were GVL sensitive. Experiments shown in E–H were in the C3H.SW→B6 model. AR1, IFNAR1–/–. P < 0.006, comparing any WT mBC-CML or IFNAR mBC-CML CD4 or CD8 recipient group with its BM-alone control; P < 0.002, comparing any mCP-CML T cell recipient group with its BM-alone control. P values determined by 2-tailed Mann-Whitney U test.