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Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors [mouse]

ABSTRACT: Phosphoinositide 3-kinase δ (PI3Kδ) plays key roles in lymphocytes and inhibitors targeting this PI3K have been approved for hematological malignancies. While preclinical data in hematological and solid tumor models have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumor immunity, the impact of PI3Kδi in human solid tumors remains unknown. Here, we assessed the effects of the PI3Kδi AMG319 in patients with early stage head and neck cancer in a neoadjuvant, double-blind and placebo-controlled randomised phase-II trial. We find that PI3Kδ inhibition decreases tumor-infiltrating TREG cells and causes heightened cytotoxic potential of tumor-infiltrating CD8+ and CD4+ T cells. Loss of intratumoral TREG cells and an increase in the frequency of activated TREG cells in the blood post-treatment are indicative of systemic effects on TREG cell tissue retention and maintenance. At the chosen AMG319 dosing, the occurrence of immune-related adverse events caused treatment discontinuation in 43% of drug-treated patients, further suggestive of systemic effects on TREG cells. Consistent with this notion, in a murine syngeneic tumor model, PI3Kδi caused a decrease in TREG cells in both tumor and non-malignant tissues and affected TREG subtype composition, maintenance and functionality.

ORGANISM(S): Mus musculus

PROVIDER: GSE166149 | GEO | 2022/03/02

REPOSITORIES: GEO

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Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors [human]

Project description:Phosphoinositide 3-kinase δ (PI3Kδ) plays key roles in lymphocytes and inhibitors targeting this PI3K have been approved for hematological malignancies. While preclinical data in hematological and solid tumor models have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumor immunity, the impact of PI3Kδi in human solid tumors remains unknown. Here, we assessed the effects of the PI3Kδi AMG319 in patients with early stage head and neck cancer in a neoadjuvant, double-blind and placebo-controlled randomised phase-II trial. We find that PI3Kδ inhibition decreases tumor-infiltrating TREG cells and causes heightened cytotoxic potential of tumor-infiltrating CD8+ and CD4+ T cells. Loss of intratumoral TREG cells and an increase in the frequency of activated TREG cells in the blood post-treatment are indicative of systemic effects on TREG cell tissue retention and maintenance. At the chosen AMG319 dosing, the occurrence of immune-related adverse events caused treatment discontinuation in 43% of drug-treated patients, further suggestive of systemic effects on TREG cells. Consistent with this notion, in a murine syngeneic tumor model, PI3Kδi caused a decrease in TREG cells in both tumor and non-malignant tissues and affected TREG subtype composition, maintenance and functionality.

2022-03-02 | GSE166148 | GEO

Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors

Project description:Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors

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