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Cited by 498Peptidase Inhibition and AnalysisPancreatic and Hepatic Oncology ResearchCancer Cells and Metastasis

Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells

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Lo, Albert, Wang, Liang-Chuan S., Scholler, John, Monslow, James, Avery, Diana, Newick, Kheng, O'Brien, Shaun, Evans, Rebecca A. +8 more·2015·Cancer Research
DOI 10.1158/0008-5472.can-14-3041PMC PMC4506263

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Abstract

Malignant cells drive the generation of a desmoplastic and immunosuppressive tumor microenvironment. Cancer-associated stromal cells (CASC) are a heterogeneous population that provides both negative and positive signals for tumor cell growth and metastasis. Fibroblast activation protein (FAP) is a marker of a major subset of CASCs in virtually all carcinomas. Clinically, FAP expression serves as an independent negative prognostic factor for multiple types of human malignancies. Prior studies established that depletion of FAP+ cells inhibits tumor growth by augmenting antitumor immunity. However, the potential for immune-independent effects on tumor growth have not been defined. Herein, we demonstrate that FAP+ CASCs are required for maintenance of the provisional tumor stroma because depletion of these cells, by adoptive transfer of FAP-targeted chimeric antigen receptor (CAR) T cells, reduced extracellular matrix proteins and glycosaminoglycans. Adoptive transfer of FAP-CAR T cells also decreased tumor vascular density and restrained growth of desmoplastic human lung cancer xenografts and syngeneic murine pancreatic cancers in an immune-independent fashion. Adoptive transfer of FAP-CAR T cells also restrained autochthonous pancreatic cancer growth. These data distinguish the function of FAP+ CASCs from other CASC subsets and provide support for further development of FAP+ stromal cell-targeted therapies for the treatment of solid tumors. Cancer Res; 75(14); 2800–10. ©2015 AACR.

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Authors
Lo, A., Wang, L.-C. S., Scholler, J., Monslow, J., Avery, D., Newick, K., O'Brien, S., Evans, R. A., Bajor, D. J., Clendenin, C., Durham, A. C., Buza, E. L., Vonderheide, R. H., June, C. H., Albelda, S. M., & Puré, E.
Affiliations
  • University of Pennsylvania (US)
  • 3Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 2Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania.
Corresponding author
Puré, Ellen
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2015-07-14
Volume
75
Issue
14
Pages
2800-2810
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-14-3041
PMC
PMC4506263
OpenAlex
W1952391983
Cited by
498
References
3
Citations by year
2026: 31 · 2025: 36 · 2024: 49 · 2023: 65 · 2022: 62 · 2021: 60 · 2020: 53 · 2019: 48 · 2018: 34 · 2017: 25 · 2016: 29 · 2015: 5 · 2012: 1
FWCI
13.54
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (T32HL007775)
  • National Cancer Institute (P01 CA 66726-07, R01CA057341, R21CA169741, R01CA141144, P01CA066726, R01CA169123, R01CA172921, R01CA051497, P30CA016520)
Topics
  • Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
desmoplasia, fibroblast activation protein, tumor microenvironment, extracellular matrix, glycosaminoglycans, tumor stroma, pancreatic cancer, lung cancer, tumor microvessel density
MeSH terms
Fibroblast Activation Protein Alpha, Animals, Extracellular Matrix, Humans, Membrane Proteins, Mice, Inbred C57BL, Neoplasms, Endopeptidases, Serine Endopeptidases, Tumor Cells, Cultured, Mice, SCID, Mice, Inbred NOD, Stromal Cells, Gelatinases, Mice, Knockout, Mice, Epithelial-Mesenchymal Transition, Tumor Microenvironment

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