Propionyl-CoA carboxylase subunit B modulates PIK3CA-regulated immune-surveillance in a pancreatic cancer mouse model.

Pancreatic ductal adenocarcinomas (PDACs) are resistant to systemic treatments including immunotherapy. Over 90% of PDACs have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Previously, we demonstrated that genetic ablation of PI3K isoform, Pik3ca in the KPC ( Kras G12D ; Trp53 R172H ; Pdx1-Cre ) pancreatic cancer cell line induced complete tumor elimination by infiltrating T cells in a mouse model. However, clinical trials using PI3K inhibitors for PDAC patients exhibited limited efficacy due to drug resistance. To identify potential contributors to PI3K inhibitor resistance, we conducted an in vivo genome-wide gene-deletion screen using the Pik3ca -/- KPC (named αKO) cells implanted in the mouse pancreas and discovered propionyl-CoA carboxylase subunit B (PCCB) modulates PIK3CA - mediated immune evasion. Deletion of Pccb gene in αKO cells (named p-αKO) allowed tumor progression causing death of host mice even though p-αKO tumors are infiltrated with T cells. Single-cell RNA sequencing revealed that infiltrating clonally expanded T cells in p-αKO tumors were more exhausted as compared to T cells founds in αKO tumors. Blockade of PD-L1/PD1 interaction reversed T cell exhaustion, slowed tumor growth and improved the survival of mice implanted with p-αKO cells. These results indicate that propionyl-CoA carboxylase activity modulates PIK3CA-regulated immune surveillance of PDAC.