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 6

Impact of p110δ inactivation on T cell antileukemia response.

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Impact of p110δ inactivation on T cell antileukemia response. p110δWT/WT...
p110δWT/WT and p110δD910A/D910A mice after adoptive transfer with 2 × 107 secondary Eμ-TCL1 leukemia cells. (A) Percentage CD5+CD19+ of CD45+ cells was examined by flow cytometry on days 0, 7, and 14. (B–G) Absolute number of CD4+ T cells (B), absolute number of CD8+ T cells (C), effector CD4+ T cells (percentage CD44loCD62LhiCD4+ of CD4+ cells) (D), effector CD8+ T cells (percentage CD44loCD62LhiCD8+ of CD8+ cells) (E), memory CD4+ T cells (percentage CD44hiCD62LhiCD4+ of CD4+ cells) (F), and memory CD8+ T cells (percentage CD44hiCD62LhiCD8+ of CD8+ cells) (G) were examined before the engraftment (Pre) and day 14 after the engraftment (Post). Black circles, p110δWT/WT; green squares, p110δD910A/D910A-R; red triangles, p110δD910A/D910A-NR. Comparisons were based on separate mixed-effects models (log-transformed data); P values were adjusted using Holm’s procedure. (H) OVA-TCL1 cells were adoptively transferred into p110δWT/WT and p110δD910A/D910A mice; OVA-specific CD8+ T cells were examined weekly using fluorescent tagged OVA tetramer by flow cytometry. Bars represent mean ± SD. (Group comparisons are based on mixed-effects models on log-transformed data; P values were adjusted for multiple comparisons using Holm’s procedure; 9 total time points examined.)