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

Published version
Peer-reviewed

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Authors

Lim, Ee Lyn 
Cugliandolo, Fiorella M 
Rosner, Dalya R 
Gyori, David 
Roychoudhuri, Rahul  ORCID logo  https://orcid.org/0000-0002-5392-1853

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.

Description

Keywords

Adaptive immunity, Cancer immunotherapy, Immunology, Oncology, Signal transduction, Animals, Antigens, Neoplasm, Antineoplastic Agents, Immunological, Antineoplastic Combined Chemotherapy Protocols, Cancer Vaccines, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases, Costimulatory and Inhibitory T-Cell Receptors, Diphtheria Toxin, Disease Models, Animal, Drug Interactions, Female, Humans, Lymphocyte Depletion, Male, Mice, Neoplasms, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Purines, Quinazolinones, Signal Transduction, T-Lymphocytes, Cytotoxic, T-Lymphocytes, Regulatory, Treatment Outcome

Journal Title

JCI Insight

Conference Name

Journal ISSN

2379-3708
2379-3708

Volume Title

3

Publisher

American Society for Clinical Investigation
Sponsorship
Wellcome Trust (095198/Z/10/Z)
Wellcome Trust (105663/Z/14/Z)
MRC (1947452)
ELL was supported by the Yousef Jameel Scholarship (Cambridge Trust). DG was funded by a grant from Karus Therapeutics Ltd. RR and KO received institute support from Biotechnology and Biological Sciences Research Council (BBSRC) BBS/E/B/000C0407, - C0409, -C0427 and -C0428 and project grant BB/N007794/1. RR was supported by Wellcome Trust grant 105663/Z/14/Z. KO was also supported by Wellcome Trust grant 095198/Z/10/Z.