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

Abstract

ABSTRACTPancreatic 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,Pik3cain the KPC (KrasG12D;Trp53R172H;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 anin vivogenome-wide gene-deletion screen using thePik3ca-/-KPC (named αKO) cells implanted in the mouse pancreas and discovered propionyl-CoA carboxylase subunit B (PCCB) modulates PIK3CA-mediated immune evasion. Deletion ofPccbgene 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.