Matte-Martone et al. observed that the relative resistance of certain leukemias to the graft-versus-leukemia effect is a consequence of differing levels of stimulation by IFN-γ needed to sensitize leukemia cells to T cell killing. These results provide opportunity to consider clinical approaches to modulate IFN-γ to prevent relapse after allogeneic stem cell transplantation.
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-gamma stimulation, whereas CP-CML MHC upregulation was independent of both the IFN-gamma receptor (IFN-gammaR) and the IFN-gamma/gamma receptor IFNAR1. Importantly, IFN-gammaR-deficient BC-CML and AML were completely resistant to CD4- and CD8-mediated GVL, whereas IFN-gammaR/IFNAR1 double-deficient CP-CML was fully GVL sensitive. Mouse AML and BC-CML stem cells were MHCI+ without IFN-gamma stimulation, suggesting that IFN-gamma sensitizes these leukemias to T cell killing by mechanisms other than MHC upregulation. Our studies identify the requirement of IFN-gamma stimulation as a mechanism for BC-CML and AML GVL resistance, whereas independence from IFN-gamma renders CP-CML more GVL sensitive, even with a lower-level alloimmune response.
Author Info: (1) Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. (2) Department of Medicine, University of Pittsburgh School of Medicine, University of
Author Info: (1) Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. (2) Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA. (3) Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA. (4) Department of Computational Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. (5) Department of Immunology, St. Jude Children's Research Hospital, Memphis Tennessee, USA. (6) Department of Microbiology and Pathology, University of Iowa, Iowa City, Iowa, USA. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA. (7) Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA. Department of Microbiology and Pathology, University of Iowa, Iowa City, Iowa, USA. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
