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Targeting CXCL12 From FAP-expressing Carcinoma-Associated Fibroblasts Synergizes With anti-PD-L1 Immunotherapy in Pancreatic Cancer

Targeting CXCL12 From FAP-expressing Carcinoma-Associated Fibroblasts Synergizes With anti-PD-L1 Immunotherapy in Pancreatic Cancer

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

Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20212-7.

PMID: 24277834

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248638	Stromal Cell-Derived Factor 1α/pre-B Cell Growth Stimulating Factor from mouse			Price
IAR4248681	SDF-1alpha (CXCL12) from mouse			Price

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