Enhanced Complement Expression in the Tumor Microenvironment Following Neoadjuvant Therapy: Implications for Immunomodulation and Survival in Pancreatic Ductal Adenocarcinoma Article Swipe
YOU?
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· 2023
· Open Access
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· DOI: https://doi.org/10.1101/2023.10.26.564099
Purpose Neoadjuvant therapy (NAT) is increasingly being used for pancreatic ductal adenocarcinoma (PDAC) treatment. However, its distinct effects on carcinoma cells and the tumor microenvironment (TME) are not fully understood. This study employs spatial transcriptomics and single-cell RNA sequencing to investigate how NAT differentially remodels PDAC’s carcinoma cells and TME. Experimental Design We used spatial transcriptomics to compare gene expression profiles in carcinoma cells and the TME between NAT-treated and NAT-naïve PDAC patients and correlated with their clinicopathologic features. Complementary single-nucleus RNA sequencing (snRNA-seq) analysis was conducted to validate our findings and identify cell types driving NAT-induced gene expression alterations. Results We found NAT not only induces apoptosis and inhibits proliferation in carcinoma cells but also significantly remodels the TME. Notably, NAT induces a coordinated upregulation of multiple key complement genes (C3, C1S, C1R, C4B and C7) in the TME, making the complement pathway one of the most significantly affected pathways by NAT. Patients with higher TME complement expression following NAT exhibit improved overall survival; more immunomodulatory and neurotrophic cancer-associated fibroblasts (CAFs); more CD4 + T cells, monocytes and mast cells; and lower immune exhaustion gene expression. snRNA-seq analysis demonstrates C3 complement upregulation specifically in CAFs but not in other stroma cell types. Conclusions Our findings indicate that NAT may reduce immunosuppression in PDAC by enhancing complement production and signaling within the TME. These findings suggest that local complement dynamics could serve as a novel biomarker for prognosis, evaluating treatment response and resistance, and guiding therapeutic strategies in NAT-treated PDAC patients. Translational Relevance As neoadjuvant therapy (NAT) increasingly becomes the preferred approach in treating resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC), there is a growing demand for novel biomarkers specifically tailored for post-NAT PDAC patients. Our study focused on how NAT differentially remodels the tumor cells and the tumor microenvironment (TME). We demonstrate that NAT can enhance local complement production and signaling in PDAC’s TME, which is associated with reduced immune exhaustion and improved overall survival. Our results highlight the importance of local complement dynamics in influencing treatment response, resistance, and overall clinical outcomes in PDAC. This new mechanism provides new opportunities in biomarker development which could facilitate more accurate prognostication and precise treatment stratification, particularly for patients undergoing NAT in PDAC.
Related Topics
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2023.10.26.564099
- https://www.biorxiv.org/content/biorxiv/early/2023/12/15/2023.10.26.564099.full.pdf
- OA Status
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- Cited By
- 1
- References
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- Related Works
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- OpenAlex ID
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Raw OpenAlex JSON
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https://openalex.org/W4388015365Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2023.10.26.564099Digital Object Identifier
- Title
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Enhanced Complement Expression in the Tumor Microenvironment Following Neoadjuvant Therapy: Implications for Immunomodulation and Survival in Pancreatic Ductal AdenocarcinomaWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2023Year of publication
- Publication date
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2023-10-30Full publication date if available
- Authors
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Xiaofei Zhang, Ruoxin Lan, Yongjun Liu, Venu G. Pillarisetty, Danting Li, Chaohui L Zhao, Suparna A. Sarkar, Weiguo Liu, Iman Hanna, Mala Gupta, Cristina Hajdu, Jonathan Melamed, Jessica Widmer, John Allendorf, Yaozhong LiuList of authors in order
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https://doi.org/10.1101/2023.10.26.564099Publisher landing page
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https://www.biorxiv.org/content/biorxiv/early/2023/12/15/2023.10.26.564099.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
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greenOpen access status per OpenAlex
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https://www.biorxiv.org/content/biorxiv/early/2023/12/15/2023.10.26.564099.full.pdfDirect OA link when available
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Tumor microenvironment, Biology, Cancer research, Transcriptome, Downregulation and upregulation, Gene expression, Gene, Biochemistry, Tumor cellsTop concepts (fields/topics) attached by OpenAlex
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1Total citation count in OpenAlex
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2025: 1Per-year citation counts (last 5 years)
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52Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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