AUTHOR=Chandrasekaran Sanjay , Funk Christopher Ronald , Kleber Troy , Paulos Chrystal M. , Shanmugam Mala , Waller Edmund K. 

TITLE=Strategies to Overcome Failures in T-Cell  Immunotherapies by Targeting PI3K-δ and –γ

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.718621

DOI=10.3389/fimmu.2021.718621

ISSN=1664-3224

ABSTRACT=<p>PI3K-δ and PI3K-γ are critical regulators of T-cell differentiation, senescence, and metabolism. PI3K-δ and PI3K-γ signaling can contribute to T-cell inhibition <italic>via</italic> intrinsic mechanisms and regulation of suppressor cell populations, including regulatory T-cells and myeloid derived suppressor cells in the tumor. We examine an exciting new role for using selective inhibitors of the PI3K δ- and γ-isoforms as modulators of T-cell phenotype and function in immunotherapy. Herein we review the current literature on the implications of PI3K-δ and -γ inhibition in T-cell biology, discuss existing challenges in adoptive T-cell therapies and checkpoint blockade inhibitors, and highlight ongoing efforts and future directions to incorporate PI3K-δ and PI3K-γ as synergistic T-cell modulators in immunotherapy.</p>