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Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors
Ee Lyn Lim, … , Rahul Roychoudhuri, Klaus Okkenhaug
Ee Lyn Lim, … , Rahul Roychoudhuri, Klaus Okkenhaug
Published June 7, 2018
Citation Information: JCI Insight. 2018;3(11):e120626. https://doi.org/10.1172/jci.insight.120626.
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Research Article Immunology Oncology

Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors

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Abstract

Multiple modes of immunosuppression restrain immune function within tumors. We previously reported that phosphoinositide 3-kinase δ (PI3Kδ) inactivation in mice confers resistance to a range of tumor models by disrupting immunosuppression mediated by regulatory T cells (Tregs). The PI3Kδ inhibitor idelalisib has proven highly effective in the clinical treatment of chronic lymphocytic leukemia and the potential to extend the use of PI3Kδ inhibitors to nonhematological cancers is being evaluated. In this work, we demonstrate that the antitumor effect of PI3Kδ inactivation is primarily mediated through the disruption of Treg function, and correlates with tumor dependence on Treg immunosuppression. Compared with Treg-specific PI3Kδ deletion, systemic PI3Kδ inactivation is less effective at conferring resistance to tumors. We show that PI3Kδ deficiency impairs the maturation and reduces the capacity of CD8+ cytotoxic T lymphocytes (CTLs) to kill tumor cells in vitro, and to respond to tumor antigen–specific immunization in vivo. PI3Kδ inactivation antagonized the antitumor effects of tumor vaccines and checkpoint blockade therapies intended to boost the CD8+ T cell response. These findings provide insights into mechanisms by which PI3Kδ inhibition promotes antitumor immunity and demonstrate that the mechanism is distinct from that mediated by immune checkpoint blockade.

Authors

Ee Lyn Lim, Fiorella M. Cugliandolo, Dalya R. Rosner, David Gyori, Rahul Roychoudhuri, Klaus Okkenhaug

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Figure 1

Deletion of phosphoinositide 3-kinase δ (PI3Kδ) in regulatory T cells (Tregs) mimics the effects of Treg depletion, but systemic PI3Kδ inactivation is less effective.

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Deletion of phosphoinositide 3-kinase δ (PI3Kδ) in regulatory T cells (T...
(A) Diphtheria toxin (DTx) was administered i.p. on days 3, 7, and 10 after s.c. tumor injection into the flank on day 0 (n = 6). EL4-OVA, MC38-OVA, and LLC-OVA tumors were removed on days 14, 24, and 18 after implantation, respectively. Proportions of Tregs in the blood of non–tumor-bearing mice (n = 2) were measured 24 hours after administration, and again immediately before the subsequent dose. (B) Proportion of tumor-infiltrating Tregs in the EL4-OVA, MC38-OVA, and LLC-OVA tumors at the time of collection. (C) Masses of EL4-OVA, MC38-OVA, and LLC-OVA tumors removed from WT or Foxp3DTR mice as described in A. (D) Masses of EL4-OVA, MC38-OVA, and LLC-OVA tumors removed from WT or Foxp3cre-PI3Kδfl mice. (E) Masses of EL4-OVA (n = 10), MC38-OVA (n = 8), and LLC-OVA (n = 8) tumors in WT or PI3KδD910A mice. (F) Proportion of tumor-infiltrating Foxp3+ Tregs in WT or PI3KδD910A mice; representative FACS plots of tumor-infiltrating lymphocytes are shown. Statistical significance was determined by multiple t tests with Holm-Sidak correction (B and F) or Mann-Whitney test (C, D, and E). *P < 0.05; **P < 0.01; ***P < 0.001. n.s., not significant.
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