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

2013; National Academy of Sciences; Volume: 110; Issue: 50 Linguagem: Inglês

10.1073/pnas.1320318110

1091-6490

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

Nanoplatforms for cancer theranostics

Significance Cancer immune evasion is well described. In some cases, this may be overcome by enhancing T-cell responses. We show that despite the presence of antitumor T cells, immunotherapeutic antibodies are ineffective in a murine pancreatic cancer model recapitulating the human disease. Removing the carcinoma-associated fibroblast (CAF) expressing fibroblast activation protein (FAP) from tumors permitted immune control of tumor growth and uncovered the efficacy of these immunotherapeutic antibodies. FAP + CAFs are the only tumoral source of chemokine (C-X-C motif) ligand 12 (CXCL12), and administering AMD3100, an inhibitor of chemokine (C-X-C motif) receptor 4, a CXCL12 receptor, also revealed the antitumor effects of an immunotherapeutic antibody and greatly diminished cancer cells. These findings may have wide clinical relevance because FAP + cells are found in almost all human adenocarcinomas.