PI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression
Shuai Dong, … , Amy J. Johnson, John C. Byrd
Shuai Dong, … , Amy J. Johnson, John C. Byrd
Published November 19, 2018
Citation Information: J Clin Invest. 2019;129(1):122-136. https://doi.org/10.1172/JCI99386.
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Research Article Hematology Immunology

PI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression

Abstract

Targeted therapy with small molecules directed at essential survival pathways in leukemia represents a major advance, including the phosphatidylinositol-3′-kinase (PI3K) p110δ inhibitor idelalisib. Here, we found that genetic inactivation of p110δ (p110δD910A/D910A) in the Eμ-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, p110δ inactivation led to rectal prolapse in mice resembling autoimmune colitis in patients receiving idelalisib. Moreover, we showed that p110δ inactivation in the microenvironment protected against CLL and acute myeloid leukemia. After receiving higher numbers of TCL1 leukemia cells, half of p110δD910A/D910A mice spontaneously recovered from high disease burden and resisted leukemia rechallenge. Despite disease resistance, p110δD910A/D910A mice exhibited compromised CD4+ and CD8+ T cell response, and depletion of CD4+ or CD8+ T cells restored leukemia. Interestingly, p110δD910A/D910A mice showed significantly impaired Treg expansion that associated with disease clearance. Reconstitution of p110δD910A/D910A mice with p110δWT/WT Tregs reversed leukemia resistance. Our findings suggest that p110δ inhibitors may have direct antileukemic and indirect immune-activating effects, further supporting that p110δ blockade may have a broader immune-modulatory role in types of leukemia that are not sensitive to p110δ inhibition.

Authors

Shuai Dong, Bonnie K. Harrington, Eileen Y. Hu, Joseph T. Greene, Amy M. Lehman, Minh Tran, Ronni L. Wasmuth, Meixiao Long, Natarajan Muthusamy, Jennifer R. Brown, Amy J. Johnson, John C. Byrd

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Figure 2

Global p110δ kinase inactivation delays spontaneous leukemia development.

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Global p110δ kinase inactivation delays spontaneous leukemia development...
(A) p110δ WT/WTTCL1 (n = 43–65) and p110δ D910A/D910ATCL1 (n = 9–39) mice were monitored monthly for leukemia development through immunophenotyping of CD5+CD19+ cells in the peripheral blood by flow cytometry. (B) Time to leukemia (leukemia is determined by having ≥10% CD5+CD19+ of total CD45+ cells in blood) of p110δWT/WTTCL1 (n = 61) and p110δD910A/D910ATCL1 mice (n = 44). (Log-rank test P < 0.001.) (C) Spleen weight from 9-month-old p110δWT/WTTCL1 and p110δD910A/D910ATCL1 mice. (Wilcoxon rank sum test P = 0.003.) (D) Lymphocytes from spleen and bone marrow were obtained from p110δWT/WTTCL1 (n = 3–10) and p110δD910A/D910ATCL1 mice (n = 4–11) 5, 7, 9, and 11 months of age. CD5+CD19+ cells were examined by flow cytometry. (Group comparisons from mixed-effects models using log-transformed data. P values within each organ were adjusted for multiple comparisons using Holm’s procedure.) Bars represent mean ± SD. (E) Histology of spleen, liver, and lung from p110δWT/WTTCL1 (n = 10) and p110δD910A/D910ATCL1 mice (n = 10) at 9 months of age. Original magnification, ×60.