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Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma

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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.

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Abbreviations

7-ADD:

7-Amino-actinomycin D

APC:

Allophycocyanin

CAF:

Cancer-associated fibroblast

CCL7:

Chemokine ligand 7

CFSE:

Carboxyfluorescein succinimidyl ester

Cy:

Cyanine

FAP:

Fibroblast activation protein

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

HGF:

Hepatocyte growth factor

HNSCC:

Head and neck squamous cell carcinoma

IGF:

Insulin-like growth factor

IL:

Interleukin

IPA:

Ingenuity pathway analysis

MMP:

Matrix metalloproteinase

NF:

Normal fibroblast

NSCLC:

Non-small cell lung cancer

SMA:

Smooth muscle actin

TGF:

Transforming growth factor

TME:

Tumor microenvironment

Treg:

Regulatory T cells

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This work was supported in part by KAKENHI (Grants-in-Aid for Scientific Research) (15K10798 to Koichi Sakakura, 25861525 to Minoru Toyoda, 26670736 to Kazuaki Chikamatsu). We thank Dr. Theresa L. Whiteside for her critical reading and comments.

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Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22, Maebashi, Gunma, 371-8511, Japan

    Hideyuki Takahashi, Koichi Sakakura, Minoru Toyoda & Kazuaki Chikamatsu

  2. Division of Integrate Oncology Research, Gunma University Initiative for Advanced Research, 3-39-22, Maebashi, Gunma, 371-8511, Japan

    Reika Kawabata-Iwakawa

  3. Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, 3-39-22, Maebashi, Gunma, 371-8511, Japan

    Susumu Rokudai & Masahiko Nishiyama

Authors
  1. Hideyuki Takahashi
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  2. Koichi Sakakura
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  3. Reika Kawabata-Iwakawa
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  4. Susumu Rokudai
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  5. Minoru Toyoda
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  7. Kazuaki Chikamatsu
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Correspondence to Kazuaki Chikamatsu.

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Takahashi, H., Sakakura, K., Kawabata-Iwakawa, R. et al. Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma. Cancer Immunol Immunother 64, 1407–1417 (2015). https://doi.org/10.1007/s00262-015-1742-0

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