
PIK3CAの欠損により誘導される膵がん細胞への強力な免疫応答は、PCCB欠損によって抑制される。PD-1/PD-L1経路の阻害により、PCCB欠損膵がん細胞への抗腫瘍性T細胞の活性化が回復する。


coremsg

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 ( Kras G12D; Trp53 R172H; Pdx1-Cre ) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca -/- KPC (named αKO) cancer cells induces clonal expansion of cytotoxic T cells infiltrating the pancreatic tumors. 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 αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene ( Pccb ) in αKO cells (named p-αKO) leads to immune evasion, tumor progression and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally expanded CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally expanded T cells infiltrating p-αKO tumors, leading to 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 cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.

### Competing Interest Statement

The authors have declared no competing interest.

Propionyl-CoA carboxylase subunit B regulates anti-tumor T cells in a pancreatic cancer mouse model

pik3ca欠損膵がんマウスモデルにおけるプロピオニルcoaカルボキシラーゼサブユニットbによる免疫監視の調節


PIK3CA欠損膵がんマウスモデルにおけるプロピオニルCoAカルボキシラーゼサブユニットBによる免疫監視の調節
