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Akt inhibition improves long-term tumour control following radiotherapy by altering the microenvironment.

ABSTRACT: Radiotherapy is an important anti-cancer treatment, but tumour recurrence remains a significant clinical problem. In an effort to improve outcomes further, targeted anti-cancer drugs are being tested in combination with radiotherapy. Here, we have studied the effects of Akt inhibition with AZD5363. AZD5363 administered as an adjuvant after radiotherapy to FaDu and PE/CA PJ34 tumours leads to long-term tumour control, which appears to be secondary to effects on the irradiated tumour microenvironment. AZD5363 reduces the downstream effectors VEGF and HIF-1?, but has no effect on tumour vascularity or oxygenation, or on tumour control, when administered prior to radiotherapy. In contrast, AZD5363 given after radiotherapy is associated with marked reductions in tumour vascular density, a decrease in the influx of CD11b⁺ myeloid cells and a failure of tumour regrowth. In addition, AZD5363 is shown to inhibit the proportion of proliferating tumour vascular endothelial cells in vivo, which may contribute to improved tumour control with adjuvant treatment. These new insights provide promise to improve outcomes with the addition of AZD5363 as an adjuvant therapy following radiotherapy.

SUBMITTER: Searle EJ

PROVIDER: S-EPMC5709765 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Akt inhibition improves long-term tumour control following radiotherapy by altering the microenvironment.

Searle Emma J EJ Telfer Brian A BA Mukherjee Debayan D Forster Duncan M DM Davies Barry R BR Williams Kaye J KJ Stratford Ian J IJ Illidge Tim M TM

EMBO molecular medicine 20171201 12

Radiotherapy is an important anti-cancer treatment, but tumour recurrence remains a significant clinical problem. In an effort to improve outcomes further, targeted anti-cancer drugs are being tested in combination with radiotherapy. Here, we have studied the effects of Akt inhibition with AZD5363. AZD5363 administered as an adjuvant after radiotherapy to FaDu and PE/CA PJ34 tumours leads to long-term tumour control, which appears to be secondary to effects on the irradiated tumour microenvironm ...[more]

PMID: 29084756

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Project description:The normal response to influenza A infection is to remain asymptomatic; indeed, a study of volunteers who tested positive for antibodies against 2009 H1N1 revealed that a majority did not experience symptoms. However, studies of influenza pandemics since the 20th century, and to a lesser degree seasonal flu, suggest that pregnancy increases influenza-associated morbidity and mortality. The confounding effect of pregnancy has been well established to adversely alter the clinical course of influenza, with short term complications to mother and baby apparent, and long-term consequences to the fetus hypothesized. However, how the condition of pregnancy impacts long-term maternal anti-influenza immunity remains contentious; while vaccination studies suggest humoral responses sufficient for protection, published research on adaptive immune responses against influenza formed during pregnancy is limited. This study expands upon published work from our lab and others by comprehensively examining compartmental and systemic changes following pandemic A/California/07/2009 influenza infection. Previously, we linked seasonal influenza infection to clinical observations of adverse outcomes in pregnancy, enhanced lung and placental histopathology, and reduced control of viral replication in lungs of infected pregnant mothers. Here, we observe that the results of a lower infectious dose of pandemic influenza are similar to that of seasonal influenza. Importantly, we expand upon work which suggests infection during pregnancy may also affect humoral immunity. Our observations of reduced early antibody hemagglutinin inhibition and virus neutralization which resolved within 8 weeks of delivery demonstrate that influenza infection impacts antibody maturation mechanisms without alterations to B cell frequency or antibody secretion. This hypothesis is further supported by plasmablast transcriptional data, which demonstrates downregulated B cell metabolism and post-translational modification systems only among pregnant animals. These findings corroborate a link between adverse pregnancy outcomes and severe pathology observed during influenza infection, and propose resolving humoral deficiencies following influenza infection confounded by pregnancy. Additional studies are required to specify the involvement of plasmablast metabolism with early humoral immunity abnormalities to best guide vaccination strategies and improve our understanding of the immunological consequences of pregnancy.

Dataset Information

Akt inhibition improves long-term tumour control following radiotherapy by altering the microenvironment.

Publications

Akt inhibition improves long-term tumour control following radiotherapy by altering the microenvironment.

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