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Single-cell RNA sequencing reveals Lin28b-dependent immune modulation in the PDAC tumor microenvironment

ABSTRACT: Cancer-associated fibroblasts (CAFs) play a crucial role in shaping the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). This study investigates the impact of an RNA-binding protein Lin28b on the immune landscape of PDAC. Single-cell RNA sequencing (scRNA-seq) was performed on orthotopic pancreatic tumors from wild-type (WT) and fibroblast-specific Lin28b knockout (Fsp-Cre;Lin28bfl/fl) mice. Our analysis revealed that Lin28b expression in CAFs promotes an immunosuppressive TME characterized by reduced immune cell infiltration and dampened type I interferon (IFN) signaling. Conversely, Lin28b deletion in CAFs resulted in increased infiltration of immune cells, particularly CD8+ T cells and enhanced cytotoxic T cell activity. These findings identify Lin28b as a CAF-intrinsic molecular brake on anti-tumor immunity and provide a rationale for targeting the Lin28 to overcome PDAC resistance to immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE306321 | GEO | 2026/06/21

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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Single-cell RNA sequencing reveals Lin28b-dependent immune modulation in the PDAC tumor microenvironment

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