Detailed Abstract
[BP Best Oral Presentation - Biliary & Pancreas (Biliary Disease/Surgery)]
[BP BO-S8] Complement-Secreting Cancer-Associated Fibroblast Remodels the Immunosuppressive Microenvironment to Promote Pancreatic Ductal Adenocarcinoma Progression
Kai CHEN 1, Bohan YANG 1, Xinxin LIU 1, Yongsu MA 1, Yinmo YANG 1, Xiaodong TIAN 1
1 Department of Hepatobiliary And Pancreatic Surgery, Peking University First Hospital, CHINA
Background : Cancer-associated fibroblast (CAF) exhibit high heterogeneity. We have identified complement-secreting CAF (csCAF) through single-cell RNA sequencing (scRNA-seq), which may play a pivotal role in modulating the pancreatic ductal adenocarcinoma (PDAC) microenvironment.
Methods : We applied single-cell multi-omics to profile csCAF in treatment-naïve PDAC, complemented by external datasets for validation. Multiplex immunohistochemistry (mIHC) was employed to delineate the spatial distribution characteristics of csCAF and its spatial relationship with other immune cells on FFPE tissue microarrays (N=215).
Results : We characterized IL6-C3+C7+OGN+APOE+ csCAF, which exhibits a unique profile distinctly divergent from inflammatory CAFs (iCAFs). csCAF presence in PDAC tissue was unambiguously established through mIHC. Remarkably, csCAF show significant infiltration in normal pancreatic tissue and early-stage PDAC (P=0.0283). Intriguingly, their infiltration conspicuously decreases in advanced PDAC. csCAF may be involved in biological processes such as matrix remodeling, angiogenesis, and complement and coagulation cascade. Pseudotime analysis suggests a potential transition of csCAF towards iCAF phenotype. Notably, csCAFs specifically express NR2F2 and ATF3 transcription factors, and can interact with ITGB1 and SDC4 on the surface of pancreatic cancer cells through CXCL12. Additionally, csCAF may collaborate with PDCD1+LAG1+ exhaustion T cells to constitute an immunosuppressive cancer ecotype.
Conclusions : csCAF is characterized by the secretion of complement, and has a potential to transform to iCAF in advanced PDAC, promoting the progression of PDAC through CXCL12-SDC4 axis.
Methods : We applied single-cell multi-omics to profile csCAF in treatment-naïve PDAC, complemented by external datasets for validation. Multiplex immunohistochemistry (mIHC) was employed to delineate the spatial distribution characteristics of csCAF and its spatial relationship with other immune cells on FFPE tissue microarrays (N=215).
Results : We characterized IL6-C3+C7+OGN+APOE+ csCAF, which exhibits a unique profile distinctly divergent from inflammatory CAFs (iCAFs). csCAF presence in PDAC tissue was unambiguously established through mIHC. Remarkably, csCAF show significant infiltration in normal pancreatic tissue and early-stage PDAC (P=0.0283). Intriguingly, their infiltration conspicuously decreases in advanced PDAC. csCAF may be involved in biological processes such as matrix remodeling, angiogenesis, and complement and coagulation cascade. Pseudotime analysis suggests a potential transition of csCAF towards iCAF phenotype. Notably, csCAFs specifically express NR2F2 and ATF3 transcription factors, and can interact with ITGB1 and SDC4 on the surface of pancreatic cancer cells through CXCL12. Additionally, csCAF may collaborate with PDCD1+LAG1+ exhaustion T cells to constitute an immunosuppressive cancer ecotype.
Conclusions : csCAF is characterized by the secretion of complement, and has a potential to transform to iCAF in advanced PDAC, promoting the progression of PDAC through CXCL12-SDC4 axis.
SESSION
BP Best Oral Presentation
Room A 3/22/2024 1:30 PM - 2:50 PM