title: Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.
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.
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, United Kingdom.
authors.forename: Christine
authors.initials: C
authors.lastname: Feig
authors.forename: James O
authors.initials: JO
authors.lastname: Jones
authors.forename: Matthew
authors.initials: M
authors.lastname: Kraman
authors.forename: Richard J B
authors.initials: RJ
authors.lastname: Wells
authors.forename: Andrew
authors.initials: A
authors.lastname: Deonarine
authors.forename: Derek S
authors.initials: DS
authors.lastname: Chan
authors.forename: Claire M
authors.initials: CM
authors.lastname: Connell
authors.forename: Edward W
authors.initials: EW
authors.lastname: Roberts
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Otavia L
authors.initials: OL
authors.lastname: Caballero
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Teichmann
authors.forename: Tobias
authors.initials: T
authors.lastname: Janowitz
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Fearon
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D001596:Benzylamines; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000628:therapy*; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D010450:Endopeptidases; D058501:Enzyme-Linked Immunospot Assay; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018093:Gelatinases / Q000378:metabolism*; D006571:Heterocyclic Compounds; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy*; D017423:Sequence Analysis, RNA; D012697:Serine Endopeptidases / Q000378:metabolism*; D019139:Tumor Escape / Q000235:genetics*; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D010450:Endopeptidases; D018093:Gelatinases; D006571:Heterocyclic Compounds; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C515256:Cxcl12 protein, mouse; C088327:plerixafor
keywords: KPC mouse; T cell exclusion; tumor immunogenicity; tumor stroma