Innate immune populations contribute to effective immune responses against B lymphoblastic leukemia cells

Abstract

Abstract Pediatric patients diagnosed with acute lymphoblastic leukemia (ALL) have a 15–20% mortality rate, in spite of current advances in therapies, including immunotherapies. Despite the use of immunotherapies in patients with relapsed or refractory ALL, relapse rates post-treatment remains over 50 percent. These observations highlight our lack of understanding of immune evasion mechanisms used by leukemia cells. Our group has previously published that IL-12 promotes a very effective immune response to B-cell ALL cells in vivo. While T cells are required to maintain remission, we observed prolonged survival in IL-12 treated Rag1−/− mice with leukemia as compared to untreated mice, suggesting a major role of the innate immune response in ALL cells. Depletion of NK cells with anti-NK1.1 did not abrogate the elimination of an immunogenic model of leukemia, in which calcineurin has been knocked down by shRNA. However, depletion of myeloid cells from immunocompetent mice using colony-stimulating factor-1 receptor (CSF1R) depleting antibodies promoted the progression of this leukemia, which was eliminated in all isotype treated, immune-competent recipients, indicating myeloid cells play a critical role in the immune response to ALL cells. Ongoing studies suggest dendritic cells (DCs), specifically CD11b+CD11c+ DCs, are reduced in mice transplanted with parental relative to immunogenic, Cn-deficient ALL cells. Furthermore, macrophages cultured in vitro with parental cells expressed significantly lower surface levels of CD80, CD40 and CD86 compared to levels found on the surface of cells cultured with Cn-deficient leukemia cells. Overall, our data suggest that ALL cells may compromise the T-cell priming capacity of innate immune cells.