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

Source: https://onco.cc/key-papers/paper-feig-cxcl12-fap-cafs-t-cell-exclusion-pnas-2013/  
OnCo record `paper-feig-cxcl12-fap-cafs-t-cell-exclusion-pnas-2013` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: PNAS
- Year: 2013
- DOI: 10.1073/pnas.1320318110
- Authors: Feig C, Jones JO, Kraman M, et al.
- 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.
- What it means: 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.

## Sources

- Feig et al., PNAS 2013: CXCL12 from FAP-positive fibroblasts excludes T cells and blocks checkpoint therapy: https://doi.org/10.1073/pnas.1320318110
- PubMed: https://pubmed.ncbi.nlm.nih.gov/24277834/

## Connected records

- cancers: [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- targets: [CTLA-4](https://onco.cc/targets/ctla4/), [CXCR4](https://onco.cc/targets/cxcr4/), [FAP](https://onco.cc/targets/fap/), [PD-L1](https://onco.cc/targets/pdl1/)
- institutions: [Cancer Research UK Cambridge Centre / CRUK Cambridge Institute](https://onco.cc/institutions/cruk-cambridge-centre/)
- pathways: [Cold tumours: immune deserts and exclusion](https://onco.cc/pathways/immune-desert-exclusion/), [Fibroblast activation, desmoplasia & matrix stiffness](https://onco.cc/pathways/caf-activation-desmoplasia/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/)
- terms: [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Immune exclusion](https://onco.cc/terms/immune-exclusion/)
- people: [David A. Tuveson](https://onco.cc/people/david-tuveson/)
- journals: [Proceedings of the National Academy of Sciences](https://onco.cc/journals/pnas/)

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