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

Nature volume 510, pages 407–411 (2014)Cite this article

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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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Figure 1: Impact of genetic inactivation of p110δ on tumour growth and metastasis.
Figure 2: Inactivation of p110δ in Treg is sufficient to confer cancer resistance.
Figure 3: Impact of p110δ inactivation on T-cell-mediated anti-tumour immunity.
Figure 4: Impact of p110δ inactivation on myeloid cells in 4T1 tumour-bearing mice.
Figure 5: Impact of pharmacological inactivation of p110δ on tumour growth and T-cell responses.

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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.

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Author notes

  1. Khaled Ali & Dalya R. Soond

    Present address: 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.).,

  2. Dalya R. Soond and Roberto Piñeiro: These authors contributed equally to this work.

  3. Klaus Okkenhaug and Bart Vanhaesebroeck: These authors jointly supervised this work.

Authors and 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.

Corresponding authors

Correspondence to Khaled Ali, Klaus Okkenhaug or Bart Vanhaesebroeck.

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Competing interests

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

Extended data figures and tables

Extended Data Figure 1 Impact of p110δ inactivation on CD4 and CD8 T cells in mice with 4T1 or EL4 tumours.

a, Levels of CD44highCD4+ and CD44highCD8+ T cells in the indicated immune compartments of naive and 4T1 tumour-bearing on day 26 after inoculation in wild-type or δD910A mice. b, Distribution of cells on day 5 of culture of splenocytes, isolated from 4T1 tumour-bearing wild-type and δD910A mice 21 days after inoculation, in the presence of mitomycin-treated 4T1 cells. c, Gene expression in CTLs derived from splenocytes from wild-type and δD910A OT-I mice, cultured in the presence of SIINFEKL OVA peptide and IL-2. GzmA, granzyme A; GzmB, granzyme B, Prf1, perforin and (FasL or CD95L) Fas ligand. Expression levels are presented relative to β2-microglobulin. *P < 0.05, **P < 0.01, ***P < 0.001 (non-parametric Mann–Whitney t-test). Numbers in brackets indicate the number of mice used per experiment. Each dot represents an individual mouse.

Extended Data Figure 2 Impact of p110δ inactivation on myeloid cells in 4T1 tumours.

a, Gating strategy used to identify myeloid cell subsets. Splenic cells were gated on CD11bhigh cells followed by Ly6C and Ly6G gating. FSC, forward scatter; SSC, side scatter (top). Frequency of CD11b+ cells in the spleen of wild-type and δD910A naïve mice and in 4T1 tumour-bearing mice on day 21 after inoculation (bottom). b, [3H]-Thymidine incorporation in co-cultures of splenocytes and purified myeloid cells, in combinations as indicated, with or without stimulation with anti-CD3 antibodies. Cultures were made using cells derived from individual mice. Error bars represent standard deviation from the mean of biological replicates. *P < 0.05, **P < 0.01 (non-parametric Mann–Whitney t-test). Numbers in brackets indicate the number of mice used per experiment. Each dot represents an individual mouse.

Extended Data Figure 3 Characterization of the p110δ-selective inhibitor PI-3065.

a, PI-3065 structure and in vitro IC50 on selected PI3K family members. No significant activity against 72 protein kinases was observed at ≤ 10 μM in a KinaseProfiler assay (Millipore). b, Pharmacokinetic parameters of PI-3065. Mean (± s.d.) plasma concentration profile of PI-3065 following a single oral dose (75 mg kg−1) administred per os (po) to female BALB/c mice. AUCinf, area under the curve, extrapolated to infinity; Cmax, highest observed plasma concentration; tmax, time at which Cmax occurred, QD, quaque die (every day). c, Growth of primary 4T1 tumours, inoculated in the breast fat pad, measured by calipers and expressed as tumour volume. Mice were dosed per os with vehicle or PI-3065 (75 mg kg−1, daily) for 36 days. 105 tumour cells were inoculated 12 h post first dosing. d, Percentage of tumour-free mice upon continuous per os treatment of mice with vehicle or PI-3065 (25 mg kg−1, twice daily) for 37 days, with tumour cells inoculated on day 7 of PI-3065 dosing. 15 mice were used for each genotype. e, Class I PI3K isoform expression in 4T1 cells. f, Proliferation of 4T1 cells following a 4-h treatment with the indicated p110δ inhibitors, washing and (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulphophenyl)-2H-tetrazolium salt (MTS) staining after 48 h culture. g, Percentage body weight change (from day 0) of 4T1 tumour-bearing mice upon daily per os administration of PI-3065 (75 mg kg−1) or vehicle for 36 consecutive days. *P < 0.05, **P < 0.01 (non-parametric Mann–Whitney t test). Numbers in brackets indicate the number of mice used per experiment.

Extended Data Table 1 Comparison of PI-3065 with Idelalisib (formerly called GS-1101 or CAL-101) and IC87114
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Ali, K., Soond, D., Piñeiro, R. et al. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 510, 407–411 (2014). https://doi.org/10.1038/nature13444

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