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 7

p110δ kinase inactivation reverses immune suppression in leukemia mice.

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p110δ kinase inactivation reverses immune suppression in leukemia mice. ...
(A) Blood from 11-month-old p110δWT/WT, p110δD910A/D910A, p110δWT/WTTCL1, and p110δD910A/D910ATCL1 mice was examined for immune checkpoint CTLA4 and PD-1 expression on CD4+ cells by flow cytometry. (Separate ANOVA models were applied to each outcome. P values within each outcome were adjusted for multiple comparisons using Holm’s procedure.) (B) Blood from 5-month-old p110δWT/WTTCL1 and p110δD910A/D910ATCL1 mice was examined for immune checkpoint PD-1 expression on CD4+ cells and leukemia burden by flow cytometry. (Group means were compared using 2-sample t tests with unequal variances.) (C) Relative Tregs (CD4+CD25+FoxP3+ of CD4+ cells) in blood and spleen of 9-month-old p110δWT/WT, p110δD910A/D910A, p110δWT/WTTCL1, and p110δD910A/D910ATCL1 mice were examined by flow cytometry. (Separate ANOVA models were applied to each outcome. P values within each outcome were adjusted for multiple comparisons using Holm’s procedure.) (D) Frequency of Tregs (CD4+CD25+FoxP3+ of CD4+ cells) in spleen was examined in p110δWT/WT and p110δD910A/D910A mice on day 14 after adoptive transfer with 2 × 107 Eμ-TCL1 secondary leukemia cells. (Differences were estimated using ANOVA.) Bars represent mean ± SD.