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Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 in pancreas 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 PDA patients, did not respond to two immunological checkpoint antagonists that promote the function of T cells, α-CTLA-4 and 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 anti-tumor 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 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 principle source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor (CXCR4) inhibitor, induced rapid T cell accumulation among cancer cells, and acted synergistically with α-PD-L1 to selectively and greatly diminish cancer cells, identified by their loss-of-heterozygosity (LOH) of Trp53. The residual tumor was comprised only of pre-malignant 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE42605 | GEO | 2012/11/30

SECONDARY ACCESSION(S): PRJNA182361

REPOSITORIES: GEO

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Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance

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2012-07-09 | E-GEOD-39205 | biostudies-arrayexpress

Mus musculus

Project description:Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 in pancreas cancer

| PRJNA182361 | ENA

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2012-07-09 | E-GEOD-39204 | biostudies-arrayexpress

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2022-10-27 | GSE209587 | GEO

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