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

• Type of Material: Article
• Authors: Sanjay Chandrasekaran, Emory University; Christopher Ronald Funk, Emory University; Troy Kleber, Emory University; Chrystal Paulos, Emory University; Malathy Shanmugam, Emory University; Edmund Waller, Emory University
• Language: English
• Date: 2021-08-26
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Chandrasekaran, Funk, Kleber, Paulos, Shanmugam and Waller
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fimmu.2021.718621
• Title of Journal or Parent Work: FRONTIERS IN IMMUNOLOGY
• Volume: 12
• Start Page: 718621
• End Page: 718621
• Grant/Funding Information: SC: NIH T32CA160040, ECOG-ACRIN Paul Carbone, MD Fellowship Award; EW: NIH 5R01AI145231-03; MS: NIH 1R01CA208328-01A1, LLS (Leukemia/Lymphoma Society) Award # 6573-19.
• Keywords: PHOSPHOINOSITIDE 3-KINASE; SUPPRESSOR-CELLS; B-CELL; immune checkpoint inhibition (ICI); SELECTIVE INHIBITOR; TIL (tumor infiltrating lymphocytes); PI3K delta; ACQUIRED-RESISTANCE; Science & Technology; PI3K gamma; METASTATIC MELANOMA; T cell differentiation; Immunology; ADOPTIVE TRANSFER; CAR T cancer therapy; CHECKPOINT BLOCKADE; adoptive cell immunotherapy; PI3K INHIBITOR; Life Sciences & Biomedicine; TUMOR-INFILTRATING LYMPHOCYTES
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology; Biology, Cell

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.