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

• 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
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.120626

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.