Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer

Stromal desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC) involves significant accumulation of type I collagen (Col1). However, the precise molecular and mechanistic contribution of Col1 in PDAC progression remains unknown. Activated pancreatic stellate cells/αSMA+ myofibroblasts are major contributors of Col1 in the PDAC stroma. We use a dual-recombinase genetic mouse model of spontaneous PDAC to delete Col1 specifically in myofibroblasts. This results in significant reduction of total stromal Col1 content and accelerates the emergence of PanINs and PDAC, decreasing overall survival. Col1 deletion leads to Cxcl5 upregulation in cancer cells via SOX9. Increase in Cxcl5 is associated with recruitment of myeloid-derived suppressor cells and suppression of CD8+ T cells, which can be attenuated with combined targeting of CXCR2 and CCR2 to restrain accelerated PDAC progression in the setting of stromal Col1 deletion. Our results unravel the fundamental role of myofibroblast-derived Co1l in regulating tumor immunity and restraining PDAC progression. [Display omitted] •Col1 deletion in myofibroblasts decreases stromal Col1 content in pancreatic tumors•Col1 deletion aggravates pancreatic tumor progression and immunosuppression•Col1 deletion promotes recruitment of CD206+ARG1+ myeloid-derived suppressor cells•CXCR2 and CCR2 inhibition reverses tumor progression promoted by Col1 deletion Chen et al. identify that the deletion of type I collagen (Col1) in αSMA+ myofibroblasts using dual-recombinase mouse models decreases stromal Col1 content and accelerates progression of pancreatic cancer. Col1 deletion promotes the recruitment of CD206+F4/80+ARG1+ myeloid-derived suppressor cells, which can be attenuated by combined inhibition of CXCR2 and CCR2.