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Propionyl-CoA carboxylase subunit B regulates anti-tumor T cells in a pancreatic cancer mouse model
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Propionyl-CoA carboxylase subunit B regulates anti-tumor T cells in a pancreatic cancer mouse model
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Journal Article
Propionyl-CoA carboxylase subunit B regulates anti-tumor T cells in a pancreatic cancer mouse model
2025
Overview
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 enrichment 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 enriched CD8 + T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched 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.
Publisher
eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
Subject
/ Animals
/ Antigens
/ Carcinoma, Pancreatic Ductal - immunology
/ Carcinoma, Pancreatic Ductal - pathology
/ Class I Phosphatidylinositol 3-Kinases - genetics
/ Class I Phosphatidylinositol 3-Kinases - metabolism
/ Cloning
/ CRISPR
/ Genes
/ Genomes
/ Genomics
/ Kinases
/ Mice
/ Pancreatic Neoplasms - immunology
/ Pancreatic Neoplasms - pathology
/ PD1
/ Programmed Cell Death 1 Receptor - metabolism
/ Propionyl-Coenzyme A Carboxylase
/ Rodents
/ T cells
/ T-Lymphocytes, Cytotoxic - immunology
/ Tumor-infiltrating lymphocytes
/ Tumors
