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


ABSTRACT: Multiple modes of immunosuppression restrain immune function within tumors. We previously reported that phosphoinositide 3-kinase ? (PI3K?) inactivation in mice confers resistance to a range of tumor models by disrupting immunosuppression mediated by regulatory T cells (Tregs). The PI3K? inhibitor idelalisib has proven highly effective in the clinical treatment of chronic lymphocytic leukemia and the potential to extend the use of PI3K? inhibitors to nonhematological cancers is being evaluated. In this work, we demonstrate that the antitumor effect of PI3K? inactivation is primarily mediated through the disruption of Treg function, and correlates with tumor dependence on Treg immunosuppression. Compared with Treg-specific PI3K? deletion, systemic PI3K? inactivation is less effective at conferring resistance to tumors. We show that PI3K? 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. PI3K? 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 PI3K? inhibition promotes antitumor immunity and demonstrate that the mechanism is distinct from that mediated by immune checkpoint blockade.

SUBMITTER: Lim EL 

PROVIDER: S-EPMC6124416 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Lim Ee Lyn EL   Cugliandolo Fiorella M FM   Rosner Dalya R DR   Gyori David D   Roychoudhuri Rahul R   Okkenhaug Klaus K  

JCI insight 20180607 11


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.  ...[more]

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