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Abstract PO-106: The extrinsic and modulatory effects of CSF-1/CSF-1R signaling in generating an immunosuppressive pancreatic cancer tumor microenvironment and promoting metastasis
- Source :
- Cancer Research. 81:PO-106
- Publication Year :
- 2021
- Publisher :
- American Association for Cancer Research (AACR), 2021.
-
Abstract
- Introduction: The multistep process of the tumor cell invasion-metastasis cascade, which involves the spread of cancer cells from primary tumor sites to colonization into distant organs, is a major barrier to effective therapy. Both intrinsic factors such as genomic instability and epigenetic alterations and extrinsic factors, such as microenvironmental cues, have been implicated in contributing to the metastatic proclivity of cancer cells. The crosstalk between tumor cells and cells within the heterogenous tumor microenvironment (TME) is a critical driver of tumorigenesis. This can nurture tumor cell migration and invasion into the stroma, providing a foundation for eventual metastasis. Using our mouse models of PDAC, we have identified Colony stimulating factor 1 (Csf-1; also known as M-Csf) to be differentially and significantly upregulated. CSF-1 is secreted by tumor cells to recruit and polarize macrophages into M2-like tumor associated macrophage (TAM) phenotype through binding to its cognate tyrosine kinase receptor colony-stimulating factor 1 receptor (CSF-1R). However, the role and mechanisms of CSF-1/CSF-1R pathway in modulating other elements of the PDAC TME that contributes to invasion and metastasis has yet to be investigated. Methods: We use Pdx1-Cre; LSL-KrasG12D/+; LSL-Trp53R172H; Rosa26LSL-YFP (KPCY) mice and 2D/3D cell culture systems. We overexpressed Csf-1 and established a CRISPR system to knockout Csf-1 in our cells using ribonucleoprotein (RNP) Cas9/gRNA complex via nucleofection. These engineered cells are used to model syngeneic primary and metastatic tumor formation. We have established a novel quantitative multiplex immunofluorescence (qmIF) staining approach to characterize changes in the TME upon modulating Csf-1 expression, specifically focusing on macrophages, myeloid-derived suppressor cell (MDSC), T-cell, B-cell, fibroblast and nerve fiber markers. Results: Our data from in vivo studies suggested that Csf-1 overexpression leads to an increase in primary tumor growth and metastasis, while the depletion of Csf-1 reduces metastatic burden. The automated quantification and analysis of our unbiased IF approaches has yielded the following: CSF-1 overexpression leads to increased tumor infiltration of F4/80+CD163+CD206+ M2-polarized macrophages and decreased number of CD3+CD8+ cytotoxic T-cells, generating an immunosuppressive TME. Furthermore, our preliminary data demonstrated that Csf-1 is also upregulated in cancer associated fibroblasts (CAFs), which potentially synergizes with the epithelial compartment to attract immunosuppressive immune cells and promote immune evasion. Finally, the TCGA data reveals that metastatic PDACs have increased Csf-1 expression compared to primary tumors and overexpression of Csf-1 is associated with reduced survival. Conclusion: We have demonstrated a novel role of CSF-1 upregulation in reprogramming the TME in PDAC and fostering increased metastatic capacity. We believe this can be exploited therapeutically. Citation Format: Gizem Efe, Kensuke Suzuki, Jason R. Pitarresi, Anna M. Chiarella, Alina L. Li, Anil K. Rustgi. The extrinsic and modulatory effects of CSF-1/CSF-1R signaling in generating an immunosuppressive pancreatic cancer tumor microenvironment and promoting metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-106.
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 81
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi...........7ec1f64abf808bfe2db513e917c237ee
- Full Text :
- https://doi.org/10.1158/1538-7445.panca21-po-106