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4078 Identification of distinct fibroblast populations with unique roles in pancreatic cancer progression and tumor immunity

Published online by Cambridge University Press:  29 July 2020

Josephine Kebbeh Darpolor
Affiliation:
The University of Texas Health Science Center at Houston
Xiaofeng Zheng
Affiliation:
The University of Texas Health Science Center at Houston
Sujuan Yang
Affiliation:
The University of Texas Health Science Center at Houston
Hikaru Sugimoto
Affiliation:
The University of Texas Health Science Center at Houston
Julienne Carstens
Affiliation:
The University of Texas Health Science Center at Houston
Pedro Correa de Sampiao
Affiliation:
The University of Texas Health Science Center at Houston
Valerie LeBleu
Affiliation:
The University of Texas Health Science Center at Houston
Raghu Kalluri
Affiliation:
The University of Texas Health Science Center at Houston
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Abstract

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OBJECTIVES/GOALS: The desmoplastic reaction in PDAC involves a significant accumulation of immune cells and fibroblasts.The functional diversity of carcinoma associated fibroblasts (CAFs) remains largely unknown, and identification of immune regulating subsets would have a substantial impact in augmentation of immunotherapy efficacy. METHODS/STUDY POPULATION: Employing histology, FACs, multiplex immunohistochemistry, single cell RNA sequencing (sc-RNA-seq) and genetically engineered mouse models, we demonstrate that aSMA+ cells are a dominant CAF population in PDAC with tumor restraining properties (TS-CAFs), as opposed those of the FAP+ CAFs, which demonstrate tumor promoting activity (TP-CAFs). RESULTS/ANTICIPATED RESULTS: Analysis of bulk tumor depleted of either TS-CAFs or TP-CAFs showed that TS-CAFs predominantly modulate extracellular matrix (ECM) production, facilitate cell-ECM adhesion and regulate adaptive immunity, while TP-CAFs exhibit a lineage that is skewed towards a pro-inflammatory, chemokine secreting phenotype. Further, scRNA-Seq analyses demonstrate that CAFs share distinct gene expression profiles characteristic of lymphocytic and myeloid lineages. Together our data distinguish two populations of CAFs, one which is tumor suppressing with roles in ECM remodeling and another which is tumor promoting with roles in cytokine production, both with immune modulating capabilities. DISCUSSION/SIGNIFICANCE OF IMPACT: Our study identifies a complex network of functionally heterogeneous fibroblasts during PDAC progression with significant immunotherapeutic implication. The identification of distinct fibroblast subsets will allow us to discriminately target fibroblast populations to augment immunotherapy efficacy in pancreatic cancer.

Type
Mechanistic Basic to Clinical
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
© The Association for Clinical and Translational Science 2020