Immune Escape of Chronic Myeloid Leukemia in Blast Crisis: The Cross-over of T cell microRNAs, Metabolism and Exhaustion

We observed that T cells from patients with blast crisis (BC) chronic myeloid leukemia (CML) lacked miR-142 and were fewer and exhausted compared with those from patients with chronic phase (CP) CML. Accordingly, the BC Mir142−/−BCR/ABL mouse also presented with T lymphopenia compared with the CP Mir142+/+BCR/ABL mouse. The miR-142 deficit impaired thymic differentiation of lymphoid-primed multipotent progenitors (LMPP) into mature T cells and redirected them toward myeloid lineage. The fewer mature T cells that emerged from LMPP differentiation in the BC mouse were enriched with exhausted T effectors. Leukemic blasts-secreted inflammatory cytokines (i.e., IL-6) mediated the miR-142 deficit, which in turn prevented the metabolic reprogramming that allows activated T cells to thrive and expand and promoted expression of the exhaustion marker PD-1. Thus, loss of miR-142 expression ultimately resulted in BC immune escape and disease growth. In fact, immunodeficient mice transplanted with BC CML LSKs and miR-142 KO T cells had shorter survival than those transplanted with BC CML LSKs and miR-142 wild-type T cells. Conversely, BC patient-derived xenograft (PDX) mice receiving autologous T cells and synthetic miR-142 mimic lived longer than those receiving autologous T cells and scramble RNA. Combination of tyrosine kinase inhibitors (TKI) plus synthetic miR-142 and/or PD-1 antibody induced a prolonged survival compared to TKI alone, suggesting that harnessing the host immune system with synthetic miR-142 may provide a novel therapeutic approach for BC CML.