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

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-α (FAP). The conditional depletion of the FAP+ 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+ 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, PDA-specific CD8+ T cells, and reveals the antitumor efficacy of the T-cell checkpoint antagonist anti–PD-L1. Recent studies have also shown that the FAP+ 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. Cancer Immunol Res; 2(3); 187–93. ©2014 AACR.