Frontiers in Immunology (Sep 2017)
PI3Kδ Inhibition Enhances the Antitumor Fitness of Adoptively Transferred CD8+ T Cells
- Jacob S. Bowers,
- Jacob S. Bowers,
- Jacob S. Bowers,
- Kinga Majchrzak,
- Kinga Majchrzak,
- Kinga Majchrzak,
- Kinga Majchrzak,
- Michelle H. Nelson,
- Michelle H. Nelson,
- Michelle H. Nelson,
- Bulent Arman Aksoy,
- Megan M. Wyatt,
- Megan M. Wyatt,
- Megan M. Wyatt,
- Aubrey S. Smith,
- Aubrey S. Smith,
- Aubrey S. Smith,
- Stefanie R. Bailey,
- Stefanie R. Bailey,
- Stefanie R. Bailey,
- Lillian R. Neal,
- Lillian R. Neal,
- Lillian R. Neal,
- Jeffrey E. Hammerbacher,
- Jeffrey E. Hammerbacher,
- Chrystal M. Paulos,
- Chrystal M. Paulos,
- Chrystal M. Paulos
Affiliations
- Jacob S. Bowers
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Jacob S. Bowers
- Department of Dermatology, Medical University of South Carolina, Charleston, SC, United States
- Jacob S. Bowers
- Department of Surgery, Medical University of South Carolina, Charleston, SC, United States
- Kinga Majchrzak
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Kinga Majchrzak
- Department of Dermatology, Medical University of South Carolina, Charleston, SC, United States
- Kinga Majchrzak
- Department of Surgery, Medical University of South Carolina, Charleston, SC, United States
- Kinga Majchrzak
- Faculty of Veterinary Medicine, Department of Physiological Sciences, Warsaw University of Life Sciences, Warsaw, Poland
- Michelle H. Nelson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Michelle H. Nelson
- Department of Dermatology, Medical University of South Carolina, Charleston, SC, United States
- Michelle H. Nelson
- Department of Surgery, Medical University of South Carolina, Charleston, SC, United States
- Bulent Arman Aksoy
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt Sinai, New York City, NY, United States
- Megan M. Wyatt
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Megan M. Wyatt
- Department of Dermatology, Medical University of South Carolina, Charleston, SC, United States
- Megan M. Wyatt
- Department of Surgery, Medical University of South Carolina, Charleston, SC, United States
- Aubrey S. Smith
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Aubrey S. Smith
- Department of Dermatology, Medical University of South Carolina, Charleston, SC, United States
- Aubrey S. Smith
- Department of Surgery, Medical University of South Carolina, Charleston, SC, United States
- Stefanie R. Bailey
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Stefanie R. Bailey
- Department of Dermatology, Medical University of South Carolina, Charleston, SC, United States
- Stefanie R. Bailey
- Department of Surgery, Medical University of South Carolina, Charleston, SC, United States
- Lillian R. Neal
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Lillian R. Neal
- Department of Dermatology, Medical University of South Carolina, Charleston, SC, United States
- Lillian R. Neal
- Department of Surgery, Medical University of South Carolina, Charleston, SC, United States
- Jeffrey E. Hammerbacher
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Jeffrey E. Hammerbacher
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt Sinai, New York City, NY, United States
- Chrystal M. Paulos
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Chrystal M. Paulos
- Department of Dermatology, Medical University of South Carolina, Charleston, SC, United States
- Chrystal M. Paulos
- Department of Surgery, Medical University of South Carolina, Charleston, SC, United States
- DOI
- https://doi.org/10.3389/fimmu.2017.01221
- Journal volume & issue
-
Vol. 8
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
