PI3Kβ controls immune evasion in PTEN-deficient breast tumours
Loss of the PTEN tumour suppressor is one of the most common oncogenic drivers across all cancer types 1 . PTEN is the major negative regulator of PI3K signalling. The PI3Kβ isoform has been shown to play an important role in PTEN-deficient tumours, but the mechanisms underlying the importance of PI...
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| Published in | Nature (London) Vol. 617; no. 7959; pp. 139 - 146 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
London
Nature Publishing Group UK
04.05.2023
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| Subjects | |
| Online Access | Get full text |
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| Summary: | Loss of the PTEN tumour suppressor is one of the most common oncogenic drivers across all cancer types
1
. PTEN is the major negative regulator of PI3K signalling. The PI3Kβ isoform has been shown to play an important role in PTEN-deficient tumours, but the mechanisms underlying the importance of PI3Kβ activity remain elusive. Here, using a syngeneic genetically engineered mouse model of invasive breast cancer driven by ablation of both
Pten
and
Trp53
(which encodes p53), we show that genetic inactivation of PI3Kβ led to a robust anti-tumour immune response that abrogated tumour growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kβ inactivation in the PTEN-null setting led to reduced STAT3 signalling and increased the expression of immune stimulatory molecules, thereby promoting anti-tumour immune responses. Pharmacological PI3Kβ inhibition also elicited anti-tumour immunity and synergized with immunotherapy to inhibit tumour growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumours upon re-challenge. Our findings demonstrate a molecular mechanism linking PTEN loss and STAT3 activation in cancer and suggest that PI3Kβ controls immune escape in PTEN-null tumours, providing a rationale for combining PI3Kβ inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.
A mouse model of invasive breast cancer in which
Pten
and
Trp53
are simultaneously inactivated links PTEN loss with STAT3 activation and indicates that immune escape in PTEN-null tumours is mediated by PI3Kβ. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 J.S.B., T.M.R. and J.J.Z. designed and guided the direction of the project. J.S.B., Qiwei W. and J.J.Z. contributed to the design, analysis and interpretation of all experiments. J.S.B. performed animal dissections, tumor/tissue manipulations and various in vitro experiments, including tissue culturing, drug treatments, virus production and transductions, western blotting, RNA isolation and Q-PCR, and analyzed flow cytometry, CyCIF, bulk RNA-Seq and scRNA-Seq data. Qiwei W. designed, performed and analyzed flow cytometry and co-culture experiments, and performed tumor/tissue manipulations and various in vitro experiments, including tissue culturing, drug treatments and transfections, CRISPR-Cas 9 editing, western blotting, RNA isolation and Q-PCR. Qi W. and J.J.Z. conceived and developed PP, PPA and PPB GEM models of breast tumors and contributed to the design of in vivo efficacy studies. M.R. and S.P. designed, performed, analyzed and interpreted scRNA-Seq experiments. W.W. and K.A-B. contributed to the design and performed in vivo drug treatments, performed tumor measurements, contributed to animal health monitoring, performed animal dissections and tumor/tissue manipulations, and performed various in vitro experiments, including tissue culturing, drug treatments, IHC, western blotting, RNA isolation, Q-PCR and ELISA. R.F. contributed to tumor measurements in vivo, and performed numerous in vitro experiments, including cloning, western blotting, RNA isolation, Q-PCR and ELISA. S.K. designed, performed and analyzed CyCIF experiments. Q.Z. and S.T. designed and performed the PPB-mPI3Kβ rescue experiments. G.K.G. designed and performed pilot immune profiling experiments by CyTOF used to guide the design of future immune profiling experiments by flow cytometry. S.X. and H.G. performed and contributed to the analysis of gene expression experiments by RNA-Seq. X.G. performed in vitro drug response experiments, western blots, Q-PCR and ELISA. T.V. and T.J. performed tumor transplantations, in vivo drug treatments and tumor measurements, and contributed to animal health monitoring. G.J.F., H-J.K. and A.K.S., contributed with key reagents, protocols and scientific discussions. J.S.B. and J.J.Z. wrote the paper. J.S.B., Qiwei W., M.R., G.K.G., G.J.F., H-J.K., A.K.S., T.M.R. and J.J.Z. reviewed and edited the manuscript. These authors contributed equally to this work Author contributions |
| ISSN: | 0028-0836 1476-4687 1476-4687 |
| DOI: | 10.1038/s41586-023-05940-w |