Journal Article

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

Kraman, Matthew, Wells, Richard J. B., Feig, Christine, Roberts, Edward W., Deonarine, Andrew, Teichmann, Sarah A., Tuveson, David A., Janowitz, Tobias, Fearon, Douglas T., Connell, Claire M., Qi Zhao, Jodrell, Duncan I., Chan, Derek S., Jones, James O., Caballero, Otavia L.

2013

Overview

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.

• Publisher: National Academy of Sciences,NATIONAL ACADEMY OF SCIENCES,National Acad Sciences
• Subject: adenocarcinoma / Analysis of Variance / Animals / antagonists / Antibodies / antineoplastic activity / Base Sequence / Benzylamines / Biological Sciences / Cancer / Carcinoma, Pancreatic Ductal - immunology / Carcinoma, Pancreatic Ductal - therapy / cell death / chemokine CXCL12 / Chemokine CXCL12 - metabolism / chemokine receptors / Chemokines / Cyclams / Cytotoxicity / Endopeptidases / Enzyme-Linked Immunospot Assay / Epithelial cells / Fibroblasts / Fibroblasts - metabolism / Flow Cytometry / Fluorescent Antibody Technique / Gelatinases - metabolism / Gene expression / genes / Heterocyclic Compounds / heterozygosity / human diseases / humans / immune evasion / Immunohistochemistry / Immunosuppression / Immunotherapy / Immunotherapy - methods / Lymphocytes / Membrane Proteins - metabolism / Mice / Molecular Sequence Data / neoplasm cells / Pancreatic cancer / pancreatic neoplasms / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - therapy / patients / Sequence Analysis, RNA / Serine Endopeptidases - metabolism / Stromal cells / T lymphocytes / Tumor Escape - genetics / Tumors