Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer

Feig, C. et al. (2013) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 110(50), pp. 20212-20217. (doi: 10.1073/pnas.1320318110) (PMID:24277834) (PMCID:PMC3864274)

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Abstract

An autochthonous model of pancreatic ductal adenocarcinoma (PDA) permitted the analysis of why immunotherapy is ineffective in this human disease. Despite finding that PDA-bearing mice had cancer cell-specific CD8+ T cells, the mice, like human patients with PDA, did not respond to two immunological checkpoint antagonists that promote the function of T cells: anti-cytotoxic T-lymphocyte-associated protein 4 (α-CTLA-4) and α-programmed cell death 1 ligand 1 (α-PD-L1). Immune control of PDA growth was achieved, however, by depleting carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). The depletion of the FAP+ stromal cell also uncovered the antitumor effects of α-CTLA-4 and α-PD-L1, indicating that its immune suppressive activity accounts for the failure of these T-cell checkpoint antagonists. Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP+ cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP+ CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. The residual tumor was composed only of premalignant epithelial cells and inflammatory cells. Thus, a single protein, CXCL12, from a single stromal cell type, the FAP+ CAF, may direct tumor immune evasion in a model of human PDA.

Item Type:Articles
Additional Information:This work was supported by Cancer Research UK (D.A.T., D.T.F.), the Wellcome Trust (D.T.F., T.J.), the Ludwig Institute for Cancer Research (D.T.F.), The Anthony Cerami and Anne Dunn Foundation for World Health (D.T.F.), the Medical Research Council (D.T.F.), Addenbrooke’s Charitable Trust (D.T.F.), and GlaxoSmith Kline (D.T.F.). This work has also been supported by the National Institute for Health Research Cambridge Biomedical Research Centre. C.F. was supported by a European Molecular Biology Organization long-term fellowship and a Marie Curie Intra European Fellowship within the Seventh European Community Framework Programme. R.J.B.W. received funding from the University of Cambridge School of Clinical Medicine, Rosetrees Trust, and Frank Edward Elmore Fund.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Roberts, Dr Ed
Authors: Feig, C., Jones, J.O., Kraman, M., Wells, R.J.B., Deonarine, A., Chan, D.S., Connell, C.M., Roberts, E.W., Zhao, Q., Caballero, O.L., Teichmann, S.A., Janowitz, T., Jodrell, D.I., Tuveson, D.A., and Fearon, D.T.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:25 November 2013

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