Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 330 (6005): 827-830

Copyright © 2010 by the American Association for the Advancement of Science

Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–{alpha}

Matthew Kraman,1,* Paul J. Bambrough,1,* James N. Arnold,1,* Edward W. Roberts,1 Lukasz Magiera,1 James O. Jones,1 Aarthi Gopinathan,2,3 David A. Tuveson,2 Douglas T. Fearon1,{dagger}

Abstract: The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein–{alpha} (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-{gamma} and tumor necrosis factor–{alpha}. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.

1 Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.
2 Cancer Research UK Cambridge Research Institute, The Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK.
3 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: dtf1000{at}

The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape from Immune Surveillance.
D. T. Fearon (2014)
Cancer Immunology 2, 187-193
   Abstract »    Full Text »    PDF »
Insidious Changes in Stromal Matrix Fuel Cancer Progression.
F. L. Miles and R. A. Sikes (2014)
Mol. Cancer Res. 12, 297-312
   Abstract »    Full Text »    PDF »
Tumoral Immune Suppression by Macrophages Expressing Fibroblast Activation Protein-{alpha} and Heme Oxygenase-1.
J. N. Arnold, L. Magiera, M. Kraman, and D. T. Fearon (2014)
Cancer Immunology 2, 121-126
   Abstract »    Full Text »    PDF »
Targeting Fibroblast Activation Protein in Tumor Stroma with Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity without Severe Toxicity.
L.-C. S. Wang, A. Lo, J. Scholler, J. Sun, R. S. Majumdar, V. Kapoor, M. Antzis, C. E. Cotner, L. A. Johnson, A. C. Durham, et al. (2014)
Cancer Immunology 2, 154-166
   Abstract »    Full Text »    PDF »
Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.
C. Feig, J. O. Jones, M. Kraman, R. J. B. Wells, A. Deonarine, D. S. Chan, C. M. Connell, E. W. Roberts, Q. Zhao, O. L. Caballero, et al. (2013)
PNAS 110, 20212-20217
   Abstract »    Full Text »    PDF »
Cancer makes new friends with old tricks.
F. Dazzi (2013)
Blood 122, 1093-1094
   Full Text »    PDF »
Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer.
H. Zhang, I. Maric, M. J. DiPrima, J. Khan, R. J. Orentas, R. N. Kaplan, and C. L. Mackall (2013)
Blood 122, 1105-1113
   Abstract »    Full Text »    PDF »
Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances.
B. P. Keenan, E. M. Jaffee, and T. D. Armstrong (2013)
Cancer Immunology 1, 16-23
   Abstract »    Full Text »    PDF »
Depletion of stromal cells expressing fibroblast activation protein-{alpha} from skeletal muscle and bone marrow results in cachexia and anemia.
E. W. Roberts, A. Deonarine, J. O. Jones, A. E. Denton, C. Feig, S. K. Lyons, M. Espeli, M. Kraman, B. McKenna, R. J. B. Wells, et al. (2013)
J. Exp. Med. 210, 1137-1151
   Abstract »    Full Text »    PDF »
Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia.
E. Tran, D. Chinnasamy, Z. Yu, R. A. Morgan, C.-C. R. Lee, N. P. Restifo, and S. A. Rosenberg (2013)
J. Exp. Med. 210, 1125-1135
   Abstract »    Full Text »    PDF »
Fibroblast-Specific Protein 1/S100A4-Positive Cells Prevent Carcinoma through Collagen Production and Encapsulation of Carcinogens.
J. Zhang, L. Chen, X. Liu, T. Kammertoens, T. Blankenstein, and Z. Qin (2013)
Cancer Res. 73, 2770-2781
   Abstract »    Full Text »    PDF »
Reading the Tea Leaves of Tumor-Mediated Immunosuppression.
R. J. Orentas (2013)
Clin. Cancer Res. 19, 955-957
   Abstract »    Full Text »    PDF »
Identification of inhibitory scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens.
J. Zhang, M. Valianou, H. Simmons, M. K. Robinson, H.-O. Lee, S. R. Mullins, W. A. Marasco, G. P. Adams, L. M. Weiner, and J. D. Cheng (2013)
FASEB J 27, 581-589
   Abstract »    Full Text »    PDF »
The Receptor for Advanced Glycation End Products Promotes Pancreatic Carcinogenesis and Accumulation of Myeloid-Derived Suppressor Cells.
P. J. Vernon, T. J. Loux, N. E. Schapiro, R. Kang, R. Muthuswamy, P. Kalinski, D. Tang, M. T. Lotze, and H. J. Zeh III (2013)
J. Immunol. 190, 1372-1379
   Abstract »    Full Text »    PDF »
Systemic Delivery of Salmonella typhimurium Transformed with IDO shRNA Enhances Intratumoral Vector Colonization and Suppresses Tumor Growth.
C. A. Blache, E. R. Manuel, T. I. Kaltcheva, A. N. Wong, J. D. I. Ellenhorn, B. R. Blazar, and D. J. Diamond (2012)
Cancer Res. 72, 6447-6456
   Abstract »    Full Text »    PDF »
The tumor microenvironment at a glance.
F. R. Balkwill, M. Capasso, and T. Hagemann (2012)
J. Cell Sci. 125, 5591-5596
   Full Text »    PDF »
Radioimmunotherapy of Fibroblast Activation Protein Positive Tumors by Rapidly Internalizing Antibodies.
E. Fischer, K. Chaitanya, T. Wuest, A. Wadle, A. M. Scott, M. van den Broek, R. Schibli, S. Bauer, and C. Renner (2012)
Clin. Cancer Res. 18, 6208-6218
   Abstract »    Full Text »    PDF »
Improving drug delivery to pancreatic cancer: breaching the stromal fortress by targeting hyaluronic acid.
P. Michl and T. M. Gress (2012)
Gut 61, 1377-1379
   Full Text »    PDF »
Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma.
J. S. Khalili, S. Liu, T. G. Rodriguez-Cruz, M. Whittington, S. Wardell, C. Liu, M. Zhang, Z. A. Cooper, D. T. Frederick, Y. Li, et al. (2012)
Clin. Cancer Res. 18, 5329-5340
   Abstract »    Full Text »    PDF »
Targeting Carcinoma-Associated Fibroblasts Within the Tumor Stroma With a Fibroblast Activation Protein-Activated Prodrug.
W. N. Brennen, D. M. Rosen, H. Wang, J. T. Isaacs, and S. R. Denmeade (2012)
J Natl Cancer Inst 104, 1320-1334
   Abstract »    Full Text »    PDF »
The Pancreas Cancer Microenvironment.
C. Feig, A. Gopinathan, A. Neesse, D. S. Chan, N. Cook, and D. A. Tuveson (2012)
Clin. Cancer Res. 18, 4266-4276
   Abstract »    Full Text »    PDF »
Release of TGF{beta}ig-h3 by gastric myofibroblasts slows tumor growth and is decreased with cancer progression.
C. Holmberg, M. Quante, I. Steele, J. D. Kumar, S. Balabanova, C. Duval, M. Czepan, Z. Rakonczay Jr, L. Tiszlavicz, I. Nemeth, et al. (2012)
Carcinogenesis 33, 1553-1562
   Abstract »    Full Text »    PDF »
Loss of Fibroblast HIF-1{alpha} Accelerates Tumorigenesis.
J.-w. Kim, C. Evans, A. Weidemann, N. Takeda, Y. S. Lee, C. Stockmann, C. Branco-Price, F. Brandberg, G. Leone, M. C. Ostrowski, et al. (2012)
Cancer Res. 72, 3187-3195
   Abstract »    Full Text »    PDF »
Cellular Constituents of Immune Escape within the Tumor Microenvironment.
S. P. Kerkar and N. P. Restifo (2012)
Cancer Res. 72, 3125-3130
   Abstract »    Full Text »    PDF »
Rationale Behind Targeting Fibroblast Activation Protein-Expressing Carcinoma-Associated Fibroblasts as a Novel Chemotherapeutic Strategy.
W. N. Brennen, J. T. Isaacs, and S. R. Denmeade (2012)
Mol. Cancer Ther. 11, 257-266
   Abstract »    Full Text »    PDF »
The White Adipose Tissue Used in Lipotransfer Procedures Is a Rich Reservoir of CD34+ Progenitors Able to Promote Cancer Progression.
I. Martin-Padura, G. Gregato, P. Marighetti, P. Mancuso, A. Calleri, C. Corsini, G. Pruneri, M. Manzotti, V. Lohsiriwat, M. Rietjens, et al. (2012)
Cancer Res. 72, 325-334
   Abstract »    Full Text »    PDF »
Nuclear Receptors as Modulators of the Tumor Microenvironment.
M. H. Sherman, M. Downes, and R. M. Evans (2012)
Cancer Prevention Research 5, 3-10
   Abstract »    Full Text »    PDF »
Novel targeted treatment strategies for refractory chronic lymphocytic leukaemia.
A. Schnaiter and S. Stilgenbauer (2011)
Therapeutic Advances in Hematology 2, 249-265
   Abstract »    PDF »
Enhancement of Cancer Vaccine Therapy by Systemic Delivery of a Tumor-Targeting Salmonella-Based STAT3 shRNA Suppresses the Growth of Established Melanoma Tumors.
E. R. Manuel, C. A. Blache, R. Paquette, T. I. Kaltcheva, H. Ishizaki, J. D. I. Ellenhorn, M. Hensel, L. Metelitsa, and D. J. Diamond (2011)
Cancer Res. 71, 4183-4191
   Abstract »    Full Text »    PDF »
Receptor Recognition of Damage/Danger Associated Molecular Pattern Molecules, Stress Signals, and HMGB1.
M. T. Lotze, W. Buchser, D. Tang, X. Liang, and H. J. Zeh (2011)
Am. Assoc. Cancer Res. Educ. Book 2011, 141-147
   Full Text »    PDF »
Awakening Immunity.
H. Schreiber and D. A. Rowley (2010)
Science 330, 761-762
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882