Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance.

ABSTRACT

Accumulating evidence suggests that cancer-associated fibroblast (CAF) macroautophagy/autophagy is crucial in tumor development and may be a therapeutic target for pancreatic ductal adenocarcinoma (PDAC). However, the role of CAF autophagy during immune surveillance and cancer immunotherapy is unclear. The present study revealed that the inhibition of CAF autophagy suppresses in vivo tumor development in immune-deficient xenografts. This deletion compromises anti-tumor immunity and anti-tumor efficacy both in vitro and in vivo by upregulating CD274/PDL1 levels in an immune-competent mouse model. A block in CAF autophagy reduced the production of IL6 (interleukin 6), disrupting high desmoplastic TME and decreasing USP14 expression at the transcription level in pancreatic cancer cells. We further identify USP14 as the post-translational factor responsible for downregulating CD274 expression by removing K63 linked-ubiquitination at the K280 residue. Finally, chloroquine diphosphate-loaded mesenchymal stem cell (MSC)-liposomes, by accurately targeting CAFs, inhibited CAF autophagy, improving the efficacy of immunochemotherapy to combat pancreatic cancer.Abbreviation AIR adaptive immune resistance; ATRA all-trans-retinoicacid; CAF cancer-associated fibroblast; CD274/PDL1 CD274 molecule; CM conditioned medium; CQ chloroquine diphosphate; CyTOF Mass cytometry; FGF2/bFGF fibroblast growth factor 2; ICB immune checkpoint blockade; IF immunofluorescence; IHC immunohistochemistry; IP immunoprecipitation; MS mass spectrometer; MSC mesenchymal stem cell; PDAC pancreatic ductal adenocarcinoma; TEM transmission electron microscopy; TILs tumor infiltrating lymphocytes; TME tumor microenvironment; USP14 ubiquitin specific peptidase 14.