GVL against mouse BC-CML and CP-CML: Shared mechanisms of T cell killing but PD-ligands render CP-CML and not BC-CML GVL-resistant

摘要

GVL against chronic phase CML (CP-CML) is potent, but it is less efficacious against acute leukemias and blast crisis CML (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 and 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 as GVL was similar against wild type or mBC-CML genetically lacking Fas, TRAIL-R, Fas/TRAIL-R, TNFR1/R2 or when donor T cells were perforin^−/−. However, mCP-CML but not mBC-CML, relied on expression of PD-ligands to resist T cell killing, as 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 that protect them from T cell killing.