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 4

Microenvironment p110δ kinase inactivation protects against CLL.

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Microenvironment p110δ kinase inactivation protects against CLL. (A–C) p...
(A–C) p110δWT/WT (n = 10) and p110δD910A/D910A mice (n = 6) were engrafted with 5 × 106 Eμ-TCL1 leukemia cells through tail vein injection. Peripheral blood disease was monitored through immunophenotyping of CD5+CD19+ cells by flow cytometry. (A) Average weekly blood disease burden. Each data point represents mean ± SD. (B) Time to leukemia (leukemia is determined by having ≥10% CD5+CD19+ of total CD45+ cells in blood) of p110δWT/WT and p110δD910A/D910A mice. (Log-rank test P = 0.215.) (C) Individual blood disease on day 31. Bars represent mean ± SD. (P = 0.004 based on 2-sample t test with unequal variances.) (D–F) p110δWT/WT (n = 10) and p110δD910A/D910A mice (n = 7) were engrafted with 5 × 106 Eμ-TCL1 leukemia cells through tail vein injection. Peripheral blood disease was monitored through immunophenotyping of CD5+CD19+ cells by flow cytometry. (D) p110δWT/WT (n = 5) and p110δD910A/D910A mice (n = 19) underwent adoptive transfer of 2 × 107 Eμ-TCL1 leukemia cells. Blood disease was monitored weekly by flow cytometry. Bars represent mean ± SD. (E) Sixty-three days after the first transfer, p110δD910A/D910A mice that had regressed disease (n = 10) and naive p110δWT/WT (n = 5) were challenged with 2 × 107 leukemic cells of the same donor Eμ-TCL1 cells. Each data point represents mean ± SD. (F) Forty-two days after the second transfer, the remaining p110δD910A/D910A (n = 9) and new naive p110δWT/WT (n = 5) mice were challenged with 2 × 107 leukemic cells from a different Eμ-TCL1 donor. Each data point represents mean ± SD.