ST2/IL-33 signaling promotes malignant development of experimental squamous cell carcinoma by decreasing NK cells cytotoxicity and modulating the intratumoral cell infiltrate
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Nádia Ghinelli Amôr1, Carine Ervolino de Oliveira1, Thaís Helena Gasparoto1, Vanessa Garcia Vilas Boas1, Graziela Perri1, Ramon Kaneno2, Vanessa Soares Lara3, Gustavo Pompermaier Garlet1, João Santana da Silva4, Gislâine A. Martins5, Cory Hogaboam6, Karen A. Cavassani7 and Ana Paula Campanelli1
1Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Dr. Octávio Pinheiro Brisolla, Bauru, SP, 17012-901, Brazil
2Department of Microbiology and Immunology, Institute of Biosciences of Botucatu, São Paulo State University, R. Prof. Dr. Antônio Celso Wagner Zanin, Botucatu, SP, 18618-689, Brazil
3Department of Stomatology – Oral Pathology, Bauru School of Dentistry, University of São Paulo, Al. Dr. Octávio Pinheiro Brisolla, Bauru, SP, 17012-901, Brazil
4Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, 14049-900, Brazil
5Department of Biomedical Sciences (Research Division of Immunology) and Medicine, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
6Department of Medicine, Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
7Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
Ana Paula Campanelli, email: firstname.lastname@example.org
Keywords: squamous cell carcinoma; IL-33; ST2; chemical carcinogenesis; immune modulation
Received: July 26, 2017 Accepted: May 19, 2018 Published: July 20, 2018
Squamous cell carcinoma (SCC) is the second most common form of skin cancer and the mechanism(s) involved in the progression of this tumor are unknown. Increases in the expression of IL-33/ST2 axis components have been demonstrated to contribute to neoplastic transformation in several tumor models and interleukin-33 is correlated with poor prognosis of patients with squamous cell carcinoma of the tongue. Based on these observations, we sought to determine the role of the IL-33/ST2 pathway during the development of SCC. Our findings show that ST2-deficiency led to a marked decrease in the severity of skin lesions, suggesting that ST2 signaling contributed to tumor development. An analysis of tumor lesions in wild-type and ST2KO mice revealed that a lack of ST2 was associated with specific and significant reductions in the numbers of CD4+ T cells, CD8+ T cells, dendritic cells, and macrophages. In addition, NK cells that were isolated from ST2KO mice exhibited higher cytotoxic activity than cells isolated from wild-type mice. Notably, ST2 deficiency resulted in lower IFN-γ, TNF-α, IL-10, and IL-17 production in tumor samples. Our findings indicate that the IL-33/ST2 pathway contributes to the development of SCC by affecting leukocyte migration to tumor microenvironment and impairing NK cytotoxic activity.
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