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

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 i...

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Bibliographic Details
Published in:JCI insight 2018-06, Vol.3 (11)
Main Authors: Lim, Ee Lyn, Cugliandolo, Fiorella M, Rosner, Dalya R, Gyori, David, Roychoudhuri, Rahul, Okkenhaug, Klaus
Format: Article
Language:English
Subjects:
Animals
Antigens, Neoplasm - administration & dosage
Antineoplastic Agents, Immunological - pharmacology
Antineoplastic Agents, Immunological - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Cancer Vaccines - pharmacology
Cancer Vaccines - therapeutic use
Cell Line, Tumor - transplantation
Class I Phosphatidylinositol 3-Kinases
Costimulatory and Inhibitory T-Cell Receptors - antagonists & inhibitors
Costimulatory and Inhibitory T-Cell Receptors - immunology
Diphtheria Toxin - administration & dosage
Disease Models, Animal
Drug Interactions
Female
Humans
Lymphocyte Depletion - methods
Male
Mice
Neoplasms - drug therapy
Neoplasms - immunology
Neoplasms - pathology
Phosphatidylinositol 3-Kinases - immunology
Phosphatidylinositol 3-Kinases - metabolism
Phosphoinositide-3 Kinase Inhibitors
Purines - pharmacology
Purines - therapeutic use
Quinazolinones - pharmacology
Quinazolinones - therapeutic use
Signal Transduction - drug effects
Signal Transduction - immunology
T-Lymphocytes, Cytotoxic - drug effects
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - immunology
Treatment Outcome
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Summary: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.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.120626