Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors.
Cugliandolo, Fiorella M
Rosner, Dalya R
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Lim, E. L., Cugliandolo, F. M., Rosner, D. R., Gyori, D., Roychoudhuri, R., & Okkenhaug, K. (2018). Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors.. JCI insight, 3 (11)https://doi.org/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 non-hematological cancers is being evaluated. In this work, we demonstrate that the anti-tumor effect of PI3Kδ inactivation is primarily mediated through the disruption of Treg function, and correlates with tumor dependence on Treg immunosuppression. Compared to 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 anti-tumor 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 anti-tumor immunity and demonstrate that the mechanism is distinct from that mediated by immune checkpoint blockade.
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.
Wellcome Trust (095198/Z/10/Z)
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External DOI: https://doi.org/10.1172/jci.insight.120626
This record's URL: https://www.repository.cam.ac.uk/handle/1810/278959
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Licence URL: http://creativecommons.org/licenses/by/4.0/
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