title: Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma.
abstract: Cancer-associated fibroblasts (CAFs) have been shown to play an important role in angiogenesis, invasion, and metastasis. In the present study, we determined whether CAFs within the tumor microenvironment (TME) in head and neck squamous cell carcinoma (HNSCC) contributed to promoting immunosuppression and evasion from immune surveillance. Six pairs of CAFs and normal fibroblasts (NFs) were established from the resected tumor tissues of patients with HNSCC. The effects of CAFs and NFs on the functions of T cells were comparatively analyzed. CAFs expressed the co-regulatory molecules, B7H1 and B7DC, whereas NFs did not. The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. Moreover, PBMCs co-cultured with the supernatants of CAFs preferentially induced T cell apoptosis and regulatory T cells over those co-cultured with the supernatants of NFs. A microarray analysis revealed that the level of genes related to the leukocyte extravasation and paxillin signaling pathways was higher in CAFs than in NFs. These results demonstrated that CAFs collaborated with tumor cells in the TME to establish an immunosuppressive network that facilitated tumor evasion from immunological destruction.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Maebashi, Gunma, 371-8511, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Maebashi, Gunma, 371-8511, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sakakura
authors.affiliation: Division of Integrate Oncology Research, Gunma University Initiative for Advanced Research, 3-39-22, Maebashi, Gunma, 371-8511, Japan.
authors.forename: Reika
authors.initials: R
authors.lastname: Kawabata-Iwakawa
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, 3-39-22, Maebashi, Gunma, 371-8511, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Rokudai
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Maebashi, Gunma, 371-8511, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyoda
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, 3-39-22, Maebashi, Gunma, 371-8511, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nishiyama
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Maebashi, Gunma, 371-8511, Japan. tikamatu@gunma-u.ac.jp.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chikamatsu
mesh_terms: D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics; D005347:Fibroblasts / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008213:Lymphocyte Activation; D020411:Oligonucleotide Array Sequence Analysis; D000077195:Squamous Cell Carcinoma of Head and Neck; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D019139:Tumor Escape
chemical_list: D016207:Cytokines
keywords: Cancer-associated fibroblasts; Head and neck squamous cell carcinoma; Immunosuppression; Regulatory T cells; T cell apoptosis