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.
Highlights
T-cell based immunotherapies aim to reinvigorate immunity against malignant cells either via infusion of effector T-cells or activation of existing T-cells in the body
We have shown that inhibition of PI3K-d and -g in T-cells with duvelisib simultaneously activates signaling through the RAS/RAF/MEK pathway [42]
A similar process of constant antigenic stimulation of the TCR is thought to occur within the cancer tumor microenvironment (TME) and contribute to establishing a population of exhausted T-cells phenotypically identified by increased expression of inhibitory receptors such as PD-1, CTLA-4, TIM-3, LAG-3, and VISTA [52, 61]
Summary
T-cell based immunotherapies aim to reinvigorate immunity against malignant cells either via infusion of effector T-cells or activation of existing T-cells in the body. Particular attention is given to how inhibition of PI3K-d and -g signaling with drug inhibitors regulates and activates pathways related to T-cell proliferation, differentiation, senescence, exhaustion, and metabolism. Constant T-cell stimulation can lead to onset of T-cell exhaustion or senescence, both dysfunctional T-cell states that share similar characteristics of reduced proliferation, cytotoxic activity, and metabolic capacity but have different underlying etiologies, cytokine profiles, and cell surface marker phenotypes [59]. A similar process of constant antigenic stimulation of the TCR is thought to occur within the cancer TME and contribute to establishing a population of exhausted T-cells phenotypically identified by increased expression of inhibitory receptors such as PD-1 (programmed cell death-1), CTLA-4 (cytotoxic T-lymphocyteassociated protein 4), TIM-3, LAG-3 (anti-lymphocyte activation gene-3), and VISTA [52, 61]. The significance of these changes in signaling pathways remains under investigation
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