Pi3k P110 Delta Inactivation Antagonizes Chronic Lymphocytic Leukemia And Reverses T Cell Immune Suppression

Targeted therapy with small molecules directed at essential survival pathways in leukemia represents a major advance, including the phosphatidylinositol-3'-kinase (PI3K) p110 delta inhibitor idelalisib. Here, we found that genetic inactivation of p110 delta (p110 delta(D910A/D910A)) in the E mu-TCL1 murine chronic lymphocytic leukemia (CLL) model impaired B cell receptor signaling and B cell migration, and significantly delayed leukemia pathogenesis. Regardless of TCL1 expression, p110 delta inactivation led to rectal prolapse in mice resembling autoimmune colitis in patients receiving idelalisib. Moreover, we showed that p110 delta inactivation in the microenvironment protected against CLL and acute myeloid leukemia. After receiving higher numbers of TCL1 leukemia cells, half of p110 delta(D910A/D910A) mice spontaneously recovered from high disease burden and resisted leukemia rechallenge. Despite disease resistance, p110 delta(D910A/D910A) mice exhibited compromised CD4(+) and CD8(+) T cell response, and depletion of CD4(+) or CD8(+) T cells restored leukemia. Interestingly, p110 delta(D910A/D910A) mice showed significantly impaired Treg expansion that associated with disease clearance. Reconstitution of p110 delta(D910A/D910A) mice with p110 delta(WT/WT) Tregs reversed leukemia resistance. Our findings suggest that p110 delta inhibitors may have direct antileukemic and indirect immune-activating effects, further supporting that p110 delta blockade may have a broader immune-modulatory role in types of leukemia that are not sensitive to p110 delta inhibition.