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 January 2, 2019; First published November 19, 2018
Citation Information: J Clin Invest. 2019;129(1):122-136. https://doi.org/10.1172/JCI99386.
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Categories: 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 5

p110δ kinase inactivation resists leukemia through a T cell–dependent mechanism.

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p110δ kinase inactivation resists leukemia through a T cell–dependent me...
(A and B) CD44+CD4+ (A) and CD44+CD8+ (B) T cells were examined in mice from Figure 3, D–F. Bars represent mean ± SD. Arrow denotes adoptive transfer of leukemia cells. A repeated-measures model was applied to the log-transformed data. For the first rechallenge, comparisons were made of day 7 and day 14 after rechallenge versus before rechallenge. For the second rechallenge, comparisons were made of day 6 and day 20 after rechallenge versus before rechallenge. (C) Eμ-TCL1 leukemia cells were adoptively transferred into p110δWT/WT (n = 5) and p110δD910A/D910A mice. p110δD910A/D910A mice were subjected to CD4-depleting (n = 9) or CD8-depleting (n = 9) antibody injections once every 3 days. Isotype controls (CD4 isotype n = 5, CD8 isotype n = 5) were included as controls. Group differences were estimated using mixed-effects models. Data represent mean ± SD. (D) Day 37 after the engraftment, p110δD910A/D910A mice in CD4 depletion, CD4 isotype, CD8 depletion, and CD8 isotype groups were euthanized. Spleen, bone marrow, and blood were analyzed for CD5+CD19+ leukemia cells. Bars represent mean ± SD. (Differences between antibody and corresponding isotype control groups were estimated using ANOVA based on the log-transformed data.)