Fang, J.-Y. | bioRxiv Science

bioRxiv2022

The effects of pks+ Escherichia coli and bile acid in colorectal tumorigenesis among people with cholelithiasis or cholecystectomy.

Patients with cholelithiasis (CL) or cholecystectomy (CE) would have more chances to get colorectal adenoma (CRA) or cancer (CRC). To figure out the effect of gut microbiota and bile acid on colorectal neoplasm in CL and CE patients, we executed a retrospective observational study recruited 463 volunteers, including 182 people with normal gallbladder (Normal), 135 CL and 146 CE patients. The discovery cohort was established to explore the difference of gut microbiota through 16S rRNA sequencing. The validation cohort aimed to verify the results of sequencing through qPCR. Through this research, significant enrichment of Escherichia coli was found in patients with cholelithiasis or cholecystectomy both in discovery cohort (PNormal-CL=0.013; PNormal-CE=0.042) and in validation cohort (PNormal-CL<0.0001; PNormal-CE<0.0001). The relative abundance of Escherichia coli was also increased in CRA and CRC patients (in discovery cohort, PHC-CRA=0.045, PHC-CRC=0.0016; in validation cohort, PHC-CRA=0.0063, PHC-CRC=0.0007). Pks+Escherichia coli was found enriched in CL and CE patients in validation cohort (PNormal-CL<0.0001; PNormal-CE<0.0001). Through KEGG analysis in discovery cohort, the differences of bile acid metabolism were revealed (Ko00120 primary bile acid biosynthesis P=0.014; Ko00121 secondary bile acid biosynthesis P=0.010). In validation cohort, we also found the elevation of serum total bile acid of CE patients (P<0.0001). And the level of serum total bile acid was found associated with the relative abundance of pks+ Escherichia coli (r=0.1895, P=0.0012). In one word, our research found that Escherichia coli, especially pks+ species, was enriched in CL and CE patients. Pks+ Escherichia coli and bile acid metabolism were associated with CRA and CRC in people after cholecystectomy.

microbiology↗

bioRxiv2020

Repurposing screen identifies Amlodipine as an inducer of PD-L1 degradation and antitumor immunity

Cancer cell expression of PD-L1 leads to T cells exhaustion by transducing co-inhibitory signal, and further understanding the regulation of PD-L1 in cancer cells may provide additional therapeutic strategies. Here by drug repurposing screen we identified amlodipine as a potent inhibitor of PD-L1 expression in cancer cells. Further survey of calcium-associated pathways revealed calpains-dependent stabilization of the PD-L1 protein. Intracellular calcium delivered an operational signal to calpain-dependent Beclin-1 cleavage, blocking autophagic degradation of PD-L1 accumulated on recycling endosome (RE). Blocking calcium flux by amlodipine depleted PD-L1 expression and increased CD8+ T cell infiltration in tumor tissues but not in myocardium, causing dose-dependent tumor suppression in vivo. Rescuing PD-L1 expression eliminated the effects of amlodipine, suggesting the PD-L1 dependent effect of amlodipine. These results reveal a calcium-dependent mechanism controlling PD-L1 degradation, and highlight calcium flux blockade as a potential strategy for combinatorial immunotherapy.

cancer biology↗