The influence of the immune system on acute lymphoblastic leukemia progression

The immune system has been proposed to have an impact on the etiology of B-cell ALL; however, a mechanistic explanation of this influence remains elusive. Epidemiological studies have uncovered a paradox, such that surrogates of infection exposure have consistently been associated with reduced ALL risk, while documented infections have a more variable influence, with both positive and negative risk associations being uncovered. Despite these contradictory findings, timing of infection exposure has been identified as a critical variable. A mechanistic explanation for the variable influences of infection or the importance of timing remain poorly defined. In this study, I use the Eµ-RET and E2A-PBX1 mouse models to assess how the basal and stimulated immune system is capable of influencing disease progression. My results indicate that in the absence of infection, resting IFN-γ is capable of influencing disease progression in the Eμ-RET mouse. By modulating SOCS-1 expression levels, IFN-γ restricted the IL-7-driven proliferation of leukemia-initiating cells (LICs) and caused a significant delay in disease progression. Furthermore, TLR ligand-mediated immune modulation inhibited disease progression by inducing the depletion of LICs through a mechanism that involved the direct activity of type-1 and type-2 interferon. Importantly, the relevance of this mechanism in humans was validated through the use of both human immune-effector and leukemia cells. Finally, I demonstrate that quantitative and qualitative differences in neonatal immune responses, in particular the increased capacity for IL-17A production by γδ T-cells, confer significant infection-induced protection from ALL progression in neonatal mice. Mechanistically these findings represent several firsts in the investigation of how the immune system influences B-cell ALL progression. They identify both type-1 and type-2 IFN and IL-17A as important inhibitory factors, and demonstrate the significant impact of immune modulation during the pre-leukemic phase on subsequent disease risk and progression. Furthermore, the results presented here provide a mechanistic explanation for the importance of timing in the association between infection exposure and ALL risk. Collectively, my results indicate that in addition to the educational influence suggested by the “delayed infection” hypothesis, early-life infection exposure may also have an active inhibitory impact on the progression of B-cell ALL.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat