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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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.
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.
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.
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.
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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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