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

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

Research output: Contribution to journalReview articlepeer-review

Abstract

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 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 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.

Original languageEnglish (US)
Article number718621
JournalFrontiers in immunology
Volume12
DOIs
StatePublished - Aug 26 2021
Externally publishedYes

Keywords

  • adoptive cell immunotherapy
  • CAR T cancer therapy
  • immune checkpoint inhibition (ICI)
  • PI3K delta
  • PI3K gamma
  • T cell differentiation
  • TIL (tumor infiltrating lymphocytes)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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