Tumor Cells and the Extracellular Matrix Dictate the Pro-Tumoral Profile of Macrophages in CRC

Cancers

Annica Barizza¹  Gaia Codolo¹  Sara Coletta¹  Marina de Bernard¹  Mario Milco D’Elios²  Chiara Della Bella²  Matteo Fassan³  Francesca Sensi⁴  Salvatore Pucciarelli⁵  Andrea Biccari⁵  Edoardo D’Angelo⁵  Marco Agostini⁶  Silvia Lonardi⁷  William Vermi⁷  Arianna Valzelli⁷ 

[1] Department of Biology, University of Padova, 35131 Padova, Italy;Department of Experimental and Clinical Medicine, University of Firenze, 50121 Firenze, Italy;Department of Medicine, Surgical Pathology Unit, University of Padova, 35124 Padova, Italy;Department of Molecular Sciences and Nanosystems, Cà Foscari University of Venice, 30172 Venice, Italy;Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, 35124 Padova, Italy;Pediatric Research Institute, 35127 Padova, Italy;Section of Pathology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy;

关键词: macrophages;    colorectal cancer;    extracellular matrix;    MHC-II;    antigen presentation;   

DOI  :  10.3390/cancers13205199

来源: DOAJ

【 摘 要 】

Tumor-associated macrophages (TAMs) are major components of the tumor microenvironment. In colorectal cancer (CRC), a strong infiltration of TAMs is accompanied by a decrease in effector T cells and an increase in the metastatic potential of CRC. We investigated the functional profile of TAMs infiltrating CRC tissue by immunohistochemistry, flow cytometry, ELISA, and qRT-PCR and their involvement in impairing the activation of effector T cells. In CRC biopsies, we evidenced a high percentage of macrophages with low expression of the antigen-presenting complex MHC-II and high expression of CD206. Monocytes co-cultured with tumor cells or a decellularized tumor matrix differentiated toward a pro-tumoral macrophage phenotype characterized by decreased expression of MHC-II and CD86 and increased expression of CD206 and an abundant release of pro-tumoral cytokines and chemokines. We demonstrated that the hampered expression of MHC-II in macrophages is due to the downregulation of the MHC-II transactivator CIITA and that this effect relies on increased expression of miRNAs targeting CIITA. As a result, macrophages become unable to present antigens to CD4 T lymphocytes. Our data suggest that the tumor microenvironment contributes to defining a pro-tumoral profile of macrophages infiltrating CRC tissue with impaired capacity to activate T cell effector functions.

【 授权许可】

Unknown