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Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer

Khaled Ali1, Dalya R Soond2, Roberto Pineiro1

  • 1UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London WC1E 6DD, UK.

Nature
|June 12, 2014
PubMed

Insights

Phosphoinositide-3-OH kinase (PI(3)K) inhibitors targeting the p110δ isoform show promise beyond leukemia. Inactivating p110δ in mice prevents various cancers by unleashing cytotoxic T cells, suggesting broader oncology applications.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) is crucial in leukocyte function.
  • PI(3)K inhibitors show efficacy in hematological malignancies like leukemia.
  • p110δ's role in solid tumors and immune tolerance is largely unexplored.

Purpose of the Study:

  • To investigate the therapeutic potential of p110δ inhibition in solid tumors.
  • To elucidate the mechanisms by which p110δ affects anti-tumor immunity.
  • To evaluate p110δ inhibitors for broader oncological applications.

Main Methods:

  • p110δ inactivation in mouse models.
  • Assessment of tumor development across various cancer types.
  • Analysis of immune cell populations and function, particularly regulatory T cells and CD8(+) T cells.
  • Tumor regression studies.

Main Results:

  • p110δ inactivation conferred protection against a wide spectrum of cancers, including solid tumors.
  • Inactivation of p110δ in regulatory T cells enhanced CD8(+) cytotoxic T cell activity.
  • Tumor regression was observed following p110δ inactivation, linked to overcoming immune tolerance.

Conclusions:

  • p110δ plays a significant role in suppressing anti-tumor immunity.
  • Targeting p110δ can break tumor-induced immune tolerance.
  • p110δ inhibitors represent a promising therapeutic strategy for a broader range of cancers, including solid tumors.

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