Letter | Published:

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

Nature volume 510, pages 407411 (19 June 2014) | Download Citation

  • A Corrigendum to this article was published on 06 April 2016

Abstract

Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias1,2. As p110δ is primarily expressed in leukocytes3, drugs against p110δ have not been considered for the treatment of solid tumours4. Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.

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Acknowledgements

This research was supported by Cancer Research UK (C23338/A10200; C23338/A15965 to B.V. and C18270/A12888 to T. Hagemann), Biotechnology and Biological Sciences Research Council (BB/E009867/1 to K.O.) and Wellcome Trust (095691/Z/11/Z) (to K.O.). We thank D. Sutherlin, J. Nonomiya, J. Lesnick and K. Reif (Genentech) for technical assistance, M. Whitehead, D. Dubuisson, D. Patton, E. Slack, N. Harrington, G. Rosignoli, W. P. Day, A. Brown, P. Depledge, F. Leenders, J. Pang, L. Salphati and X. Zhang for experimental help, D. Fearon and J. Arnold for LLC-OVA cells, and A. Rudensky for FoxP3YFP-Cre mice.

Author information

Author notes

    • Khaled Ali
    •  & Dalya R. Soond

    Present Addresses: Oncology Research, Amgen, 1120 Veterans Boulevard, South San Francisco, California 94080, USA (K.A.); University of Birmingham, School of Infection and Immunity, Centre for Translational Inflammation Research, New Queen Elizabeth Hospital Research Laboratory, Mindelsohn Way, Edgbaston, Birmingham B15 2WB, UK (D.R.S.).

    • Dalya R. Soond
    •  & Roberto Piñeiro

    These authors contributed equally to this work.

    • Klaus Okkenhaug
    •  & Bart Vanhaesebroeck

    These authors jointly supervised this work.

Affiliations

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

    • Khaled Ali
    • , Roberto Piñeiro
    • , Wayne Pearce
    •  & Bart Vanhaesebroeck
  2. Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK

    • Dalya R. Soond
    • , Ee Lyn Lim
    • , Hicham Bouabe
    • , Martin Turner
    •  & Klaus Okkenhaug
  3. Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK

    • Thorsten Hagemann
  4. Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell OX11 0RD, UK

    • Cheryl L. Scudamore
  5. Piramed Pharma, 957 Buckingham Avenue, Slough, Berkshire SL1 4NL, UK

    • Timothy Hancox
  6. Cancer Signaling and Translational Oncology, Genentech Inc, 1 DNA Way, South San Francisco, California 94080-4990, USA

    • Heather Maecker
    •  & Lori Friedman

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Contributions

K.A., D.R.S., R.P., E.L.L, H.B. and W.P. performed experiments and data analyses with input from K.O. and B.V. D.R.S. and K.O. generated the FoxP3YFP-Cre×δflox/flox mice and helped to design, perform and interpret experiments. R.P. and W.P. helped design experiments. T. Hagemann and his team carried out the KPC experiments and performed analysis with help of K.A. M.T. generated the p110δflox/flox mice. T. Hancox performed chemistry for small molecule inhibitor development. H.M. helped to design and performed in vivo pharmacological cancer experiments. L.F. helped design and interpret pharmacological data. C.L.S. performed and interpreted histopathology. K.A., K.O. and B.V. wrote the paper.

Competing interests

K.O. is consultant to GSK (Stevenage) and B.V. is a consultant to Retroscreen (London, UK) and Karus Therapeutics (Oxford, UK).

Corresponding authors

Correspondence to Khaled Ali or Klaus Okkenhaug or Bart Vanhaesebroeck.

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DOI

https://doi.org/10.1038/nature13444

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