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PI3K? Inhibition Enhances the Antitumor Fitness of Adoptively Transferred CD8+ T Cells.

ABSTRACT: Phosphatidylinositol-3-kinase p110? (PI3K?) inhibition by Idelalisib (CAL-101) in hematological malignancies directly induces apoptosis in cancer cells and disrupts immunological tolerance by depleting regulatory T cells. Yet, little is known about the direct impact of PI3K? blockade on effector T cells from CAL-101 therapy. Herein, we demonstrate a direct effect of p110? inactivation via CAL-101 on murine and human CD8+ T cells that promotes a strong undifferentiated phenotype (elevated CD62L/CCR7, CD127, and Tcf7). These CAL-101 T cells also persisted longer after transfer into tumor bearing mice in both the murine syngeneic and human xenograft mouse models. The less differentiated phenotype and improved engraftment of CAL-101 T cells resulted in stronger antitumor immunity compared to traditionally expanded CD8+ T cells in both tumor models. Thus, this report describes a novel direct enhancement of CD8+ T cells by a p110? inhibitor that leads to markedly improved tumor regression. This finding has significant implications to improve outcomes from next generation cancer immunotherapies.

SUBMITTER: Bowers JS 

PROVIDER: S-EPMC5626814 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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PI3Kδ Inhibition Enhances the Antitumor Fitness of Adoptively Transferred CD8<sup>+</sup> T Cells.

Bowers Jacob S JS   Majchrzak Kinga K   Nelson Michelle H MH   Aksoy Bulent Arman BA   Wyatt Megan M MM   Smith Aubrey S AS   Bailey Stefanie R SR   Neal Lillian R LR   Hammerbacher Jeffrey E JE   Paulos Chrystal M CM  

Frontiers in immunology 20170929

Phosphatidylinositol-3-kinase p110δ (PI3Kδ) inhibition by Idelalisib (CAL-101) in hematological malignancies directly induces apoptosis in cancer cells and disrupts immunological tolerance by depleting regulatory T cells. Yet, little is known about the direct impact of PI3Kδ blockade on effector T cells from CAL-101 therapy. Herein, we demonstrate a direct effect of p110δ inactivation <i>via</i> CAL-101 on murine and human CD8<sup>+</sup> T cells that promotes a strong undifferentiated phenotype  ...[more]

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