Cremasco and Astarita et al. analyzed murine 4T1 and human breast tumor stromal cells expressing fibroblast activation protein (FAP) and identified two subpopulations based on expression of the glycoprotein podoplanin (PDPN). FAP+PDPN+ cells expressed characteristics of fibroblasts, had increased TGFβ signaling, promoted extracellular matrix remodeling and fibrosis, contributed to the immune-excluded phenotype (potentially via chemokines or matrix effects), and suppressed CD4+ and CD8+ T cell proliferation via nitric oxide. FAP+PDPN- cells, identified as cancer-associated pericytes, did not directly suppress intratumoral T cells.
Cancer-associated fibroblasts (CAFs) are generally associated with poor clinical outcome. CAFs support tumor growth in a variety of ways and can suppress antitumor immunity and response to immunotherapy. However, a precise understanding of CAF contributions to tumor growth and therapeutic response is lacking. Discrepancies in this field of study may stem from heterogeneity in composition and function of fibroblasts in the tumor microenvironment. Furthermore, it remains unclear whether CAFs directly interact with and suppress T cells. Here, mouse and human breast tumors were used to examine stromal cells expressing fibroblast activation protein (FAP), a surface marker for CAFs. Two discrete populations of FAP+ mesenchymal cells were identified on the basis of podoplanin (PDPN) expression: a FAP+PDPN+ population of CAFs and a FAP+PDPN(-) population of cancer-associated pericytes (CAPs). Although both subsets expressed extracellular matrix molecules, the CAF transcriptome was enriched in genes associated with TGFbeta signaling and fibrosis compared with CAPs. In addition, CAFs were enriched at the outer edge of the tumor, in close contact with T cells, whereas CAPs were localized around vessels. Finally, FAP+PDPN+ CAFs suppressed the proliferation of T cells in a nitric oxide-dependent manner whereas FAP+PDPN(-) pericytes were not immunosuppressive. Collectively, these findings demonstrate that breast tumors contain multiple populations of FAP-expressing stromal cells of dichotomous function, phenotype, and location.