Autophagy affects the abundance of intratumoral bacteria and influences the prognosis of patients with pancreatic carcinoma

The role of intratumoral microbiota in pancreatic ductal adenocarcinoma (PDAC) remains controversial. We observed impaired LAMP2/LC3 colocalization and abundant pancreatic bacteria in mice deficient for the autophagy-relevant genes ATG7 or LAMP2, as well as in mice expressing the KRAS oncogene in the pancreas. We performed high-resolution immunofluorescence profiling of whole tissue sections and microbiome sequencing of surgical specimens from patients with non-metastatic PDAC neoadjuvant chemotherapy (n=62) or adjuvant (chemo-naive, n=101), along with intraductal papillary mucinous neoplasms (IPMN, n=24), chronic pancreatitis (CP, n=33) and healthy donors (n=9). We determined increased alpha and beta bacteria diversity in intratumoral tissue of adjuvant and neoadjuvant PDAC patients and in intra-pancreatic tissue from CP but not in IPMN patients compared to donor controls. Along with increased pancreatic lipopolysaccharide (LPS) and overabundant 16S rRNA FISH positive bacteria in PDAC, there is greater microbial colonization in both PDAC tissue. We detected reduced LAMP2/LC3 colocalization - reflecting reduced autophagosome/lysosome fusion - in the three pancreatic diseases compared to donor controls. Moreover, both LAMP2/LC3 colocalization and 16S rRNA FISH positivity were significantly associated with good prognosis in patients with adjuvant or neoadjuvant PDAC. Together, these findings suggest that autophagy affects the intratumoral microbiota in PDAC patients and influences PDAC prognosis.