Modeling leukemia immunoediting in mouse-human chimeras (P2169)

Abstract

Abstract Acute Myeloid Leukemia (AML) can be recognized and eliminated by the immune system, as demonstrated by the clinical efficacy of allogeneic hematopoietic stem cell transplantation. Still, immune-resistant variants of AML can outgrow upon the selective pressure of the transplanted immune system and determine clinical relapse, in a process called “leukemia immunoediting”, the biological bases of which remain largely unknown. To unravel novel mechanisms of immunoediting, we engrafted primary human AML in immunocompromised NOD/SCID γ-chainnull mice and modeled immune pressure by serial infusions of human T cells, either autologous or allogeneic to the leukemic cells. HLA-mismatched allogeneic T cells eradicated AML from 6/6 treated mice, whereas HLA-identical T cells granted only temporary control in 3/3 mice and autologous T cells were completely inefficacious in 3/3 mice. To fine-tune immune pressure from HLA-mismatched T cells, and thus model a phase of equilibrium before leukemia immune escape, we genetically modified allogeneic T cells to express the HSV-Tk suicide gene. The activation of the suicidal machinery abated circulating T cell counts in 3/3 mice, halted the ongoing antileukemic response and resulted in leukemia outgrowth. Gene expression profiling of the AML blasts purified from the mice upon escape from immune pressure demonstrated the selective and significant deregulation of genes involved in immune processes, including antigen processing and presentation.