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Neoadjuvant-induced Complement Upregulation in Tumor Microenvironment is Associated with Immunomodulation and Improved Survival in Pancreatic Ductal Adenocarcinoma: Insights from Spatially Resolved Transcriptomics

ABSTRACT: Recently neoadjuvant therapy (NAT) is being increasingly used in the treatment of pancreatic ductal adenocarcinoma (PDAC). However, how NAT differentially impacts the tumor and the tumor microenvironment (TME) is still poorly defined. Therefore, we compared the spatial transcriptomics profiles in tumor and the TME of PDACs resected from patients with versus without NAT. We found that NAT can significantly upregulate multiple key complement genes (C3, C1S, C1R, C4B and C7) in TME but not in tumor, making the complement pathway the most significantly modified pathways by NAT. In addition, the NAT-treated patients s with higher TME complement show significantly higher expression of gene signatures for immunomodulatory and neurotropic fibroblast, mast cells, CD4+ T cells and monocytes, significantly lower expression of immune exhaustion gene signature, and improved overall survival. Our results suggested that NAT may have immunostimulatory effect for PDAC through upregulating TME complement signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240078 | GEO | 2024/06/05

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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Neoadjuvant-induced Complement Upregulation in Tumor Microenvironment is Associated with Immunomodulation and Improved Survival in Pancreatic Ductal Adenocarcinoma: Insights from Spatially Resolved Transcriptomics

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