Rapid expansion of podoplanin-positive fibroblasts following radiation limits the anti-tumour CD8+ T-cell response to radiotherapy
Authors list
Anna C Wilkins Spyridon Makris Mary Green Steven Hooper Anna Mikolajczak Giovanni Giangreco Srinivas Allanki Emma Nye Emma Connick Richard Mitter Sam Cooper Emily Durie Malin Pedersen Amy Burley Katie O'Fee Ben O'Leary Daniel Shewring Zoe Ramsden Alan Melcher Kevin Harrington Navita Somaiah Sophie E Acton Erik SahaiThis article is a preprint. Preprints have not been peer-reviewed.
You can read more about preprints.
Abstract
Radiotherapy is known to cause changes in the tumour stroma which can undermine treatment efficacy. Our understanding of this process has historically centred around effects driven by Transforming Growth Factor-beta (TGF-β) and alpha-smooth muscle actin (α-SMA)+ fibroblasts. Here, we identified a rapid expansion of podoplanin (PDPN)+ fibroblasts following radiotherapy in breast, head and neck and melanoma tumours. This fibrosis was not dependent on TGF-β, but was downstream of a radiotherapy-induced adaptive immune response. CD8+ T-cells entering the tumour after radiation were sequestered at the interface between residual tumour cells and PDPN+ fibroblasts and failed to enter the tumour core. Genetic deletion of PDPN in fibroblasts impacted their cytoskeleton and ability to organise extracellular matrix. This was associated with increased CD8+ T-cell entry and spontaneous tumour regression. Overall, we identify a mechanism whereby PDPN+ fibrosis limits immune-mediated radiation cell kill and demonstrate that disruption of PDPN signalling favours tumour control.
Details
Archive
bioRxiv
Available online
Publication date
Keywords
Type of publication
