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Inactivation of PI(3)K p110? breaks regulatory T-cell-mediated immune tolerance to cancer.

ABSTRACT: Inhibitors against the p110? isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110? is primarily expressed in leukocytes, drugs against p110? have not been considered for the treatment of solid tumours. Here we report that p110? inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110? inactivation in regulatory T cells unleashes CD8(+) cytotoxic T cells and induces tumour regression. Thus, p110? inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.

SUBMITTER: Ali K

PROVIDER: S-EPMC4501086 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Ali Khaled K Soond Dalya R DR Pineiro Roberto R Hagemann Thorsten T Pearce Wayne W Lim Ee Lyn EL Bouabe Hicham H Scudamore Cheryl L CL Hancox Timothy T Maecker Heather H Friedman Lori L Turner Martin M Okkenhaug Klaus K Vanhaesebroeck Bart B

Nature 20140611 7505

Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110δ is primarily expressed in leukocytes, drugs against p110δ have not been considered for the treatment of solid tumours. 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 c ...[more]

PMID: 24919154

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Project description:Pancreatic cancer (PC) is a devastating disease characterised by late diagnosis, genetic neoplastic heterogeneity, poor T-cell infiltration, a highly immunosuppressive tumour microenvironment, and metastatic spreading which results in poor clinical outcomes. Surgery remains the most effective treatment, although it is limited to a few patients. Local ablative techniques, such as radiofrequency ablation (RFA), have been proposed to control PC progression in patients with nonresectable tumours. However, the impact of these therapies on promoting the activation of the immune system and eliciting an effective anti-tumour immune response remains elusive. Whether local ablative techniques could overcome resistance to immunotherapy in PC is unknown. We enrolled a cohort of patients with non-resectable locally advanced pancreatic cancer and longitudinally evaluated the impact of local thermal ablation on circulating immunological parameters. Additionally, we used cancer cell lines derived from PC transgenic mouse models to establish a preclinical platform that recapitulates systemic and localised inflammation induced by RFA in vivo. Finally, we employed this preclinical experimental platform to evaluate the efficacy of the therapeutic treatments. Thermal ablation induced a short-term inflammatory process resulting in a systemic increase in myeloid cells as well as increased plasma levels of high mobility group box 1 molecule, which correlates with a better patient outcome. We performed thermal ablative procedures in mice bearing orthotopic PC and evaluated the therapeutic efficacy of thermal treatment alone or in combination with immune checkpoint-based immunotherapy through activation of a T lymphocyte-dependent anti-tumour immune response. We demonstrated that RFA synergises with immunotherapy to restrict tumour progression, significantly improving the overall survival of PC-bearing mice. Tumour immune landscape characterisation confirmed that RFA in combination with immunotherapy supported the sculpting of an immune hostile milieu towards an effective anti-tumour milieu characterised by an increased infiltration of cytotoxic T lymphocytes in spite of CD206-expressing tumour-associated macrophages. Our study confirmed that RFA enhances immunotherapy effectiveness by breaking tumour immune tolerance and unleashing the full cytotoxic abilities of tumour-specific T-cells. Thus, RFA can circumvent the current limitations of immunotherapy in patients with pancreatic cancer.

Dataset Information

Inactivation of PI(3)K p110? breaks regulatory T-cell-mediated immune tolerance to cancer.

Publications

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

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