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Front Immunol. 2017 Sep 29;8:1221. doi: 10.3389/fimmu.2017.01221. eCollection 2017.

PI3Kδ Inhibition Enhances the Antitumor Fitness of Adoptively Transferred CD8+ T Cells.

Bowers JS1,2,3, Majchrzak K1,2,3,4, Nelson MH1,2,3, Aksoy BA5, Wyatt MM1,2,3, Smith AS1,2,3, Bailey SR1,2,3, Neal LR1,2,3, Hammerbacher JE1,5, Paulos CM1,2,3.

Author information

1
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States.
2
Department of Dermatology, Medical University of South Carolina, Charleston, SC, United States.
3
Department of Surgery, Medical University of South Carolina, Charleston, SC, United States.
4
Faculty of Veterinary Medicine, Department of Physiological Sciences, Warsaw University of Life Sciences, Warsaw, Poland.
5
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt Sinai, New York City, NY, United States.

Abstract

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 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 p110δ inhibitor that leads to markedly improved tumor regression. This finding has significant implications to improve outcomes from next generation cancer immunotherapies.

KEYWORDS:

CAL-101; T cell; adoptive cell therapy; cancer; idelalisib; memory; phosphatidylinositol-3-kinase

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