Pancreatic ductal adenocarcinoma (PDAC) is characterised by an
abundant desmoplastic stroma composed of cancer-associated fibroblasts
(CAF) and interspersed immune cells. A non-canonical CD8+
T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and
has been identified in tumours. Here, we evaluated the Tc17 role in
Infiltration of Tc17 cells in PDAC tissue was correlated with
patient overall survival and tumour stage. Wild-type (WT) or Il17ra-/-
quiescent pancreatic stellate cells (qPSC) were exposed to conditional
media obtained from Tc17 cells (Tc17-CM); moreover, co-culture of
Tc17-CM-induced inflammatory (i)CAF (Tc17-iCAF) with tumour cells was
performed. IL-17A/F-, IL-17RA-, RAG1-deficient and Foxn1nu/nu mice were used to study the Tc17 role in subcutaneous and orthotopic PDAC mouse models.
Increased abundance of Tc17 cells highly correlated with reduced
survival and advanced tumour stage in PDAC. Tc17-CM induced iCAF
differentiation as assessed by the expression of iCAF-associated genes
via synergism of IL-17A and TNF. Accordingly, IL-17RA controlled the
responsiveness of qPSC to Tc17-CM. Pancreatic tumour cells co-cultured
with Tc17-iCAF displayed enhanced proliferation and increased expression
of genes implicated in proliferation, metabolism and protection from
apoptosis. Tc17-iCAF accelerated growth of mouse and human tumours in Rag1-/- and Foxn1nu/nu mice, respectively. Finally, Il17ra-expressed by fibroblasts was required for Tc17-driven tumour growth in vivo.
We identified Tc17 as a novel protumourigenic CD8+
T-cell subtype in PDAC, which accelerated tumour growth via
IL-17RA-dependent stroma modification. We described a crosstalk between
three cell types, Tc17, fibroblasts and tumour cells, promoting PDAC
progression, which resulted in poor prognosis for patients.