Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–α

Kraman, Matthew; Bambrough, Paul; Arnold, James N.; Roberts, Ed; Magiera, Łukasz; Jones, James O.; Gopinathan, Aarthi; Tuveson, David A.; Fearon, Douglas T.

doi:10.1126/science.1195300

Cited by 976 publications

(897 citation statements)

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“…All experiments were performed in accordance with institutional guidelines and were approved by the UK Home Office and the animal ethics committee of Cancer Research UK Cambridge Institute and the University of Cambridge. The generation of KPC and FAP-DTR BAC transgenic mice has been described previously (9,10). These strains were crossed to generate KPCD (LSL-KrasG12D/+;LSL-Tp53R172H/+;Pdx-1-Cre;FAP-DTR) mice.…”

Section: Methodsmentioning

confidence: 99%

“…A mesenchymal tumoral stromal cell that is present in almost all human adenocarcinomas (8) and is identified by its expression of the membrane protein, fibroblast activation protein (FAP), was shown recently to mediate immunosuppression in a transplanted murine tumor model (9). Because FAP + stromal cells are present in human PDA (8), we wished to investigate whether the immunosuppressive activity of the murine FAP + stromal cell might be involved in the resistance of this cancer to immunotherapy.…”

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confidence: 99%

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

Feig

Jones

Kraman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Feig

Jones

Kraman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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1,529

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“…A mouse line was generated in which FAP þ cells were directed to express the diphtheria toxin receptor (DTR) by a modified bacterial artificial chromosome (BAC) transgene containing the fap gene (18). Administration of diphtheria toxin to these mice causes the apoptotic death of cells expressing the fap gene, regardless of whether they are actively replicating, unlike the herpes simplex viral thymidine kinase/ganciclovir method of conditionally ablating cells that does not kill resting cells.…”

Section: Background and Rationalementioning

confidence: 99%

The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape from Immune Surveillance

Fearon

2014

Cancer Immunology Research

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The fibroblastic element of the tumor microenvironment has been of great interest to cancer biologists but less so to cancer immunologists. Yet, the sharing of a common mesenchymal cell type in the stroma of tumors and at sites of chronic inflammatory lesions, some of which have an autoimmune basis, has been a strong hint that this cellular component of the tumor microenvironment may have an immunologic function. Recent studies have confirmed this possibility. These fibroblast-like cells, which are termed carcinoma-associated fibroblasts (CAF), can be identified by their expression of the membrane protein, fibroblast activation protein-a (FAP). The conditional depletion of the FAP þ CAF permits immune control not only of an artificial, transplanted tumor, but also of an autochthonous model of pancreatic ductal adenocarcinoma (PDA) that replicates the molecular, histologic, clinical, and immunologic characteristics of the human disease. Immune suppression by the FAP þ CAF is mediated by CXCL12, the chemokine that binds to cancer cells and excludes T cells by a mechanism that depends on signaling by the CXCL12 receptor CXCR4. Inhibition of CXCR4 leads to the elimination of cancer cells by enabling the rapid, intratumoral accumulation of preexisting, PDAspecific CD8 þ T cells, and reveals the antitumor efficacy of the T-cell checkpoint antagonist anti-PD-L1. Recent studies have also shown that the FAP þ CAF is related to FAP-expressing stromal cells of normal tissues, demonstrating that cancers recruit a member of an essential stromal cell lineage that is involved not only in wound repair but also in normal tissue homeostasis. These findings extend the concept introduced by cancer biologists that the fibroblastic component of tumors has a critical role in the adaptation of the cancer to the host.

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“…Whereas FAP −/− mice are phenotypically indistinct from wild-type mice (18), the stromal cell that expresses FAP mediates immune suppression in the tumor microenvironment (19,20) and maintains skeletal muscle mass and hematopoiesis (21,22). FAP + stromal cells from different organs display similar gene expression profiles, but adopt organ-specific functions, like the production of specific cytokines and chemokines.…”

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Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 ⁺ T cells

Denton

Roberts

Linterman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Fibroblastic reticular cells (FRCs), through their expression of CC chemokine ligand (CCL)19 and CCL21, attract and retain T cells in lymph nodes (LNs), but whether this function applies to both resting and activated T cells has not been examined. Here we describe a model for conditionally depleting FRCs from LNs based on their expression of the diphtheria toxin receptor (DTR) directed by the gene encoding fibroblast activation protein-α (FAP). As expected, depleting FAP + FRCs causes the loss of naïve T cells, B cells, and dendritic cells from LNs, and this loss decreases the magnitude of the B-and T-cell responses to a subsequent infection with influenza A virus. In contrast, depleting FAP + FRCs during an ongoing influenza infection does not diminish the number or continued response of activated T and B cells in the draining LNs, despite still resulting in the loss of naïve T cells. Therefore, different rules govern the LN trafficking of resting and activated T cells; once a T cell is engaged in antigen-specific clonal expansion, its retention no longer depends on FRCs or their chemokines, CCL19 and CCL21. Our findings suggest that activated T cells remain in the LN because they down-regulate the expression of the sphingosine-1 phosphate receptor-1, which mediates the exit of lymphocytes from secondary lymphoid organs. Therefore, LN retention of naïve lymphocytes and the initiation of an immune response depend on FRCs, but is an FRC independent and possibly cell-autonomous response of activated T cells, which allows the magnitude of clonal expansion to determine LN egress. viral infection | T-cell migration | lymph node stroma

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Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–α

Cited by 976 publications

References 28 publications

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

The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape from Immune Surveillance

Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 ⁺ T cells

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Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–α

Cited by 976 publications

References 28 publications

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

The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape from Immune Surveillance

Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 + T cells

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Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 ⁺ T cells