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Treg-driven tumour control by PI3Kδ inhibition limits myeloid-derived suppressor cell expansion

Sarah N Lauder1, Kathryn Smart2, Valentina M T Bart2

  • 1Division of Infection and Immunity, Cardiff University School of Medicine, SIURI, Cardiff, CF14 4XN, UK. LauderSN@cardiff.ac.uk.

British Journal of Cancer
|August 19, 2022
PubMed
Abstract

Insights

Blocking PI3Kδ with PI-3065 enhances anti-tumour T-cell response by inhibiting Tregs. This indirectly reduces myeloid-derived suppressor cells (MDSCs) by controlling tumour growth, not direct inhibition.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • PI3Kδ inhibition using PI-3065 enhances anti-tumour T-cell response via direct Treg inhibition.
  • PI-3065 treatment also reduces myeloid-derived suppressor cell (MDSC) numbers, but the mechanism is unclear.

Purpose of the Study:

  • To investigate the mechanism by which PI3Kδ inhibition affects MDSCs in a 4T1 breast cancer model.

Main Methods:

  • Utilized the 4T1 breast cancer mouse model treated with PI-3065.
  • Investigated the impact of Treg targeting independent of PI-3065.
  • Assessed MDSC numbers following surgical tumour removal.
  • Conducted ex vivo studies on cells from PI-3065-treated mice.

Main Results:

  • PI-3065 treatment reduced MDSC expansion and tumour size.
  • Independent Treg targeting also decreased tumour volume and MDSC numbers.
  • Surgical tumour removal led to a rapid decline in MDSC numbers.
  • Ex vivo studies showed PI-3065 did not directly affect MDSC activity.

Conclusions:

  • MDSCs are not directly inhibited by PI-3065.
  • Reduced MDSC recruitment and immunosuppression are indirect consequences of PI3Kδ inhibition-driven tumour control.
  • PI3Kδ inhibition enhances tumour immunity through direct (Treg) and indirect (MDSC, secondary to tumour control) mechanisms.

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