Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 50, Pages 20212-20217Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1320318110
Keywords
KPC mouse; tumor stroma; T cell exclusion; tumor immunogenicity
Categories
Funding
- National Institute for Health Research Cambridge Biomedical Research Centre
- European Molecular Biology Organization long-term fellowship
- Marie Curie Intra European Fellowship within the Seventh European Community Framework Programme
- University of Cambridge School of Clinical Medicine
- Rosetrees Trust
- Frank Edward Elmore Fund
- Cancer Research UK [15678] Funding Source: researchfish
- Medical Research Council [MC_U105161047, MC_PC_12012] Funding Source: researchfish
- National Institute for Health Research [CL-2011-14-007] Funding Source: researchfish
- MRC [MC_U105161047, MC_PC_12012] Funding Source: UKRI
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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 (alpha-CTLA-4) and alpha-programmed cell death 1 ligand 1 (alpha-PD-L1). Immune control of PDA growth was achieved, however, by depleting carcinom alpha-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). The depletion of the FAP(+) stromal cell also uncovered the antitumor effects of alpha-CTLA-4 and alpha-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 alpha-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.
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