Comparative Transcriptomic Analysis of aKO and p-aKO in Pancreatic Cancer Cells

Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. This study now shows that implantation of Pik3ca-/- KPC (named aKO) cancer cells induces clonal expansion of cytotoxic T cells infiltrating the pancreatic tumors in this mouse model. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using aKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in aKO cells (named p-aKO) leads to immune evasion, tumor progression and death of host mice. Surprisingly, p-aKO tumors are still infiltrated with T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated clonally expanded T cells infiltrating p-aKO tumors, leading slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic tumors and this understanding may help to improve immunotherapy for PDAC.