PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity
Abstract PI3K inhibitors with differential selectivity to distinct PI3K isoforms have been tested extensively in clinical trials, largely to target tumor epithelial cells. PI3K signaling also regulates the immune system and inhibition of PI3Kδ modulate the tumor immune microenvironment of pre-clinic...
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2018-12-01
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Series: | Journal for ImmunoTherapy of Cancer |
Online Access: | http://link.springer.com/article/10.1186/s40425-018-0457-0 |
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doaj-d8dfe19702e54dfe8e8186c3eeb571772020-11-25T01:42:16ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262018-12-016111410.1186/s40425-018-0457-0PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activityLarissa S. Carnevalli0Charles Sinclair1Molly A. Taylor2Pablo Morentin Gutierrez3Sophie Langdon4Anna M. L. Coenen-Stass5Lorraine Mooney6Adina Hughes7Laura Jarvis8Anna Staniszewska9Claire Crafter10Ben Sidders11Elizabeth Hardaker12Kevin Hudson13Simon T. Barry14Bioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaBioscience, Oncology, IMED Biotech Unit AstraZenecaAbstract PI3K inhibitors with differential selectivity to distinct PI3K isoforms have been tested extensively in clinical trials, largely to target tumor epithelial cells. PI3K signaling also regulates the immune system and inhibition of PI3Kδ modulate the tumor immune microenvironment of pre-clinical mouse tumor models by relieving T-regs-mediated immunosuppression. PI3K inhibitors as a class and PI3Kδ specifically are associated with immune-related side effects. However, the impact of mixed PI3K inhibitors in tumor immunology is under-explored. Here we examine the differential effects of AZD8835, a dual PI3Kα/δ inhibitor, specifically on the tumor immune microenvironment using syngeneic models. Continuous suppression of PI3Kα/δ was not required for anti-tumor activity, as tumor growth inhibition was potentiated by an intermittent dosing/schedule in vivo. Moreover, PI3Kα/δ inhibition delivered strong single agent anti-tumor activity, which was associated with dynamic suppression of T-regs, improved CD8+ T-cell activation and memory in mouse syngeneic tumor models. Strikingly, AZD8835 promoted robust CD8+ T-cell activation dissociated from its effect on T-regs. This was associated with enhancing effector cell viability/function. Together these data reveal novel mechanisms by which PI3Kα/δ inhibitors interact with the immune system and validate the clinical compound AZD8835 as a novel immunoncology drug, independent of effects on tumor cells. These data support further clinical investigation of PI3K pathway inhibitors as immuno-oncology agents.http://link.springer.com/article/10.1186/s40425-018-0457-0 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Larissa S. Carnevalli Charles Sinclair Molly A. Taylor Pablo Morentin Gutierrez Sophie Langdon Anna M. L. Coenen-Stass Lorraine Mooney Adina Hughes Laura Jarvis Anna Staniszewska Claire Crafter Ben Sidders Elizabeth Hardaker Kevin Hudson Simon T. Barry |
spellingShingle |
Larissa S. Carnevalli Charles Sinclair Molly A. Taylor Pablo Morentin Gutierrez Sophie Langdon Anna M. L. Coenen-Stass Lorraine Mooney Adina Hughes Laura Jarvis Anna Staniszewska Claire Crafter Ben Sidders Elizabeth Hardaker Kevin Hudson Simon T. Barry PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity Journal for ImmunoTherapy of Cancer |
author_facet |
Larissa S. Carnevalli Charles Sinclair Molly A. Taylor Pablo Morentin Gutierrez Sophie Langdon Anna M. L. Coenen-Stass Lorraine Mooney Adina Hughes Laura Jarvis Anna Staniszewska Claire Crafter Ben Sidders Elizabeth Hardaker Kevin Hudson Simon T. Barry |
author_sort |
Larissa S. Carnevalli |
title |
PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity |
title_short |
PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity |
title_full |
PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity |
title_fullStr |
PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity |
title_full_unstemmed |
PI3Kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity |
title_sort |
pi3kα/δ inhibition promotes anti-tumor immunity through direct enhancement of effector cd8+ t-cell activity |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2018-12-01 |
description |
Abstract PI3K inhibitors with differential selectivity to distinct PI3K isoforms have been tested extensively in clinical trials, largely to target tumor epithelial cells. PI3K signaling also regulates the immune system and inhibition of PI3Kδ modulate the tumor immune microenvironment of pre-clinical mouse tumor models by relieving T-regs-mediated immunosuppression. PI3K inhibitors as a class and PI3Kδ specifically are associated with immune-related side effects. However, the impact of mixed PI3K inhibitors in tumor immunology is under-explored. Here we examine the differential effects of AZD8835, a dual PI3Kα/δ inhibitor, specifically on the tumor immune microenvironment using syngeneic models. Continuous suppression of PI3Kα/δ was not required for anti-tumor activity, as tumor growth inhibition was potentiated by an intermittent dosing/schedule in vivo. Moreover, PI3Kα/δ inhibition delivered strong single agent anti-tumor activity, which was associated with dynamic suppression of T-regs, improved CD8+ T-cell activation and memory in mouse syngeneic tumor models. Strikingly, AZD8835 promoted robust CD8+ T-cell activation dissociated from its effect on T-regs. This was associated with enhancing effector cell viability/function. Together these data reveal novel mechanisms by which PI3Kα/δ inhibitors interact with the immune system and validate the clinical compound AZD8835 as a novel immunoncology drug, independent of effects on tumor cells. These data support further clinical investigation of PI3K pathway inhibitors as immuno-oncology agents. |
url |
http://link.springer.com/article/10.1186/s40425-018-0457-0 |
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