{"entity":{"id":"paper-feig-cxcl12-fap-cafs-t-cell-exclusion-pnas-2013","kind":"paper","name":"Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer","aka":[],"tldr":"Mice with pancreatic cancer had tumour-specific T cells but did not respond to checkpoint drugs; the fibroblasts were coating the cancer cells with a chemical, CXCL12, that kept T cells away, and blocking it let the T cells in and made anti-PD-L1 work.","summary":"An autochthonous model of pancreatic ductal adenocarcinoma allowed analysis of why immunotherapy is ineffective. Despite cancer cell-specific CD8 T cells, mice did not respond to anti-CTLA-4 or anti-PD-L1. Depleting FAP-expressing carcinoma-associated fibroblasts achieved immune control and uncovered the antitumour effects of both checkpoint antagonists. T cells were absent from regions containing cancer cells, cancer cells were coated with CXCL12, and the FAP-positive CAF was the principal source of it. AMD3100, a CXCR4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with anti-PD-L1, leaving a residual tumour of premalignant epithelial and inflammatory cells.","asOf":"2026-09-24","links":[{"label":"Feig et al., PNAS 2013: CXCL12 from FAP-positive fibroblasts excludes T cells and blocks checkpoint therapy","url":"https://doi.org/10.1073/pnas.1320318110"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/24277834/"}],"tags":[],"related":[],"cancers":["pancreatic"],"sections":[],"technologies":[],"targets":["fap","cxcr4","pdl1","ctla4"],"drugs":[],"companies":[],"institutions":["cruk-cambridge-centre"],"pathways":["immune-desert-exclusion","caf-activation-desmoplasia","pd1-checkpoint"],"terms":["immune-exclusion","cold-vs-hot"],"trials":[],"people":["david-tuveson"],"bottlenecks":[],"keyPapers":[],"journals":["pnas"],"dependsOn":[],"notes":[],"journal":"PNAS","year":2013,"doi":"10.1073/pnas.1320318110","pmid":"24277834","authors":"Feig C, Jones JO, Kraman M, et al.","paperType":"basic","findings":["FAP-positive CAFs are the principal source of CXCL12, which coats cancer cells and excludes T cells.","CXCR4 inhibition let T cells in and synergised with anti-PD-L1."],"whatItMeans":"The mechanistic account of T-cell exclusion that all later combination immunotherapy trials in pancreatic cancer cite, and the origin of CXCR4 inhibitor combinations.","caveats":["Mouse model; human CXCR4 inhibitor trials have been small.","FAP depletion is not clinically available."],"changedPractice":false},"route":"/key-papers/paper-feig-cxcl12-fap-cafs-t-cell-exclusion-pnas-2013/","neighbours":{"cancer":[{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"target":[{"id":"ctla4","kind":"target","name":"CTLA-4","route":"/targets/ctla4/"},{"id":"cxcr4","kind":"target","name":"CXCR4","route":"/targets/cxcr4/"},{"id":"fap","kind":"target","name":"FAP","route":"/targets/fap/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"}],"institution":[{"id":"cruk-cambridge-centre","kind":"institution","name":"Cancer Research UK Cambridge Centre / CRUK Cambridge Institute","route":"/institutions/cruk-cambridge-centre/"}],"pathway":[{"id":"immune-desert-exclusion","kind":"pathway","name":"Cold tumours: immune deserts and exclusion","route":"/pathways/immune-desert-exclusion/"},{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","route":"/pathways/caf-activation-desmoplasia/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"}],"term":[{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"immune-exclusion","kind":"term","name":"Immune exclusion","route":"/terms/immune-exclusion/"}],"person":[{"id":"david-tuveson","kind":"person","name":"David A. Tuveson","route":"/people/david-tuveson/"}],"journal":[{"id":"pnas","kind":"journal","name":"Proceedings of the National Academy of Sciences","route":"/journals/pnas/"}]}}