Strategies to Overcome Failures in T-Cell Immunotherapies by Targeting PI3K-delta and -gamma

PI3K-delta and PI3K-gamma are critical regulators of T-cell differentiation, senescence, and metabolism. PI3K-delta and PI3K-gamma signaling can contribute to T-cell inhibition via 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 delta- and gamma-isoforms as modulators of T-cell phenotype and function in immunotherapy. Herein we review the current literature on the implications of PI3K-delta and -gamma 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-delta and PI3K-gamma as synergistic T-cell modulators in immunotherapy.