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

TLDR

Cancer immune evasion is well described, and boosting T‑cell responses can sometimes overcome it. In a murine pancreatic cancer model, anti‑PD‑L1 antibodies alone failed, but removal of FAP‑expressing CAFs or CXCL12/CXCR4 blockade restored tumor control and uncovered antibody efficacy, underscoring the clinical relevance of targeting FAP+ cells in most adenocarcinomas.

Abstract

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.