Role of the macrophage migration inhibitory factor (MIF) in the modulation of the tumor associated macrophages in oral squamous cell carcinoma

Author(s)

Mariana Barbosa de Souza Rizzo

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2019-10-31

Examining board members

Marcos Brasilino de Carvalho; Gilberto de Castro Junior; Adriana Madeira Álvares da Silva

• Advisor: Marcos Brasilino de Carvalho

Abstract

INTRODUCTION. Inflammation is present in the different stages of carcinogenesis and progression of most malignant neoplasms. Cancerassociated inflammation, including tumor-associated macrophages, plays different mechanisms depending on the type and frequency of stimuli received, and may thus display anti or tumor functions. Macrophage Migration Inhibitory Factor (MIF) plays an active role in the modulation of tumor immune response and prior studies have shown that it can induce immunosuppressive and protumor phenotype in macrophages located in the stroma of malignant neoplasms. However, this phenomenon is still poorly understood in tumors of the head and neck, particularly oral squamous cell carcinoma (OSCC). OBJECTIVES. The present study aimed to assess the modulation of macrophages phenotype by OSCC and the role of the MIF protein in this mechanism. METHODS. In murine models, RAW 264.7 macrophages and bone marrow-derived macrophages from C57BL/6 WT, MIFKO or CD74KO mice were cocultured with SCCVII oral câncer cells. In human models, macrophages derived from peripheral blood monocytes from 3 healthy donors and macrophages derived from the U937 monocyte lineage were co-cultured with SCC9 and/or SCC25 oral câncer cells. When needed for the experiment, inhibition of MIF protein was done by treatment with 4-IPP and treatment with IL-4 was used to induce the alternate profile of macrophages. The phenotypic profile of macrophages was evaluated by qRT-PCR and/or WB. RESULTS. In the murine models studied, OSCC induced the phenotypic alteration of macrophages and this effect was predominantly dependent on the macrophagic expression of the MIF protein. OSCC and IL4 were shown to collaborate for the induction of even higher levels of ARG1 expression by macrophages and this activation was also dependent on the MIF protein. In the human models, OSCC cells were able to induce markers of alternative phenotype in macrophages derived from peripheral blood monocytes from different individuals and also in macrophages derived from U937 monocytes. Participation of the MIF protein in the induction of the alternative phenotype by OSCC or IL4 was observed but was not consistent among the different human models studied. CONCLUSIONS. OSCC induced the expression of immunosuppressive and pro-tumor phenotype markers in murine and human macrophages. MIF protein was found to participate in the modulation of macrophages by OSCC and may be a potential target in the inhibition of tumor-associated macrophages as a therapeutic intervention for this neoplasm (AU)

• FAPESP's process: 15/02584-5 - The role of the Macrophage Migration Inhibitory Factor in the modulation of the tumor inflammatory infiltrate and progression of oral squamous cell carcinoma
• Grantee: MARIANA BARBOSA DE SOUZA RIZZO
• Support Opportunities: Scholarships in Brazil - Doctorate