title: Graft-versus-leukemia (GVL) against mouse blast-crisis chronic myelogenous leukemia (BC-CML) and chronic-phase chronic myelogenous leukemia (CP-CML): shared mechanisms of T cell killing, but programmed death ligands render CP-CML and not BC-CML GVL resistant.
abstract: Graft-versus-leukemia (GVL) against chronic-phase chronic myelogenous leukemia (CP-CML) is potent, but it is less efficacious against acute leukemias and blast-crisis chronic myelogenous leukemia (BC-CML). The mechanisms underlying GVL resistance are unknown. Previously, we found that alloreactive T cell targeting of GVL-sensitive bcr-abl-induced mouse CP-CML (mCP-CML) required TCR-MHC interactions and that multiple and redundant killing mechanisms were in play. To better understand why BC-CML is resistant to GVL, we performed a comprehensive analysis of GVL against mouse BC-CML (mBC-CML) induced by the retroviral transfer of the bcr-abl and NUP98/HOXA9 fusion cDNAs. Like human BC-CML, mBC-CML was GVL resistant, and this was not due to accelerated kinetics or a greater leukemia burden. To study T cell recognition and killing mechanisms, we generated a panel of gene-deficient leukemias by transducing bone marrow from gene-deficient mice. T cell target recognition absolutely required that mBC-CML cells express MHC molecules. GVL against both mCP-CML and mBC-CML required leukemia expression of ICAM-1. We hypothesized that mBC-CML would be resistant to some of the killing mechanisms sufficient to eliminate mCP-CML, but we found instead that the same mechanisms were effective against both types of leukemia, because GVL was similar against wild-type or mBC-CML genetically lacking Fas, TRAIL-R, Fas/TRAIL-R, or TNFR1/R2 or when donor T cells were perforin(-/-). However, mCP-CML, but not mBC-CML, relied on expression of programmed death-1 ligands 1 and 2 (PD-L1/L2) to resist T cell killing, because only GVL against mCP-CML was augmented when leukemias lacked PD-L1/L2. Thus, mBC-CML cells have cell-intrinsic mechanisms, distinct from mCP-CML cells, which protect them from T cell killing.
authors.affiliation: Department of Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Matte-Martone
authors.forename: Srividhya
authors.initials: S
authors.lastname: Venkatesan
authors.forename: Hung Sheng
authors.initials: HS
authors.lastname: Tan
authors.forename: Ioanna
authors.initials: I
authors.lastname: Athanasiadis
authors.forename: Julia
authors.initials: J
authors.lastname: Chang
authors.forename: Jovana
authors.initials: J
authors.lastname: Pavisic
authors.forename: Warren D
authors.initials: WD
authors.lastname: Shlomchik
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology*; D001752:Blast Crisis / Q000235:genetics / Q000276:immunology*; D016313:Genes, abl / Q000276:immunology; D020544:Graft vs Leukemia Effect / Q000235:genetics / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000276:immunology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000276:immunology; D012190:Retroviridae; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic
chemical_list: D051017:Apoptosis Regulatory Proteins; D018398:Homeodomain Proteins; C400441:NUP98-HOXA9 fusion protein, human; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion