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Role of human Breast Cancer-derived extracellular vesicles in immune regulation and acquired drug resistance

Grant number: 19/25826-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): August 01, 2020
Effective date (End): February 29, 2024
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Fausto Bruno dos Reis Almeida
Grantee:Patrick Wellington da Silva dos Santos
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Cancer cells actively release extracellular vesicles, including exosomes, into the tumor microenvironment. Tumor exosomes carry a range of regulatory molecules and represent one of the communication pathways between the tumor and adjacent cells. Exosomes are involved in the process of chemoresistance by expelling drugs into the extracellular environment. There is evidence of the participation of tumor exosomes in signaling pathways related to chemoresistance, but the mechanisms have not yet been elucidated. In addition to promoting chemoresistance, invasion, metastasis, and angiogenesis, exosomes also collaborate with the maintenance of tumor immune evasion. Tumor exosomes can modulate leukocyte response by several different mechanisms. For example, tumor exosomes polarize macrophages into a pro-tumor phenotype and inhibit the action of CD8 + T lymphocytes (CTLs). Despite the immunosuppressive function, tumor exosomes can carry specific antigens, making them recognizable by leukocytes. Dendritic cell exosomes may activate the cytolytic activity of CTLs in the tumor microenvironment. However, there is little information on the role of isolated leukocyte exosomes in modulating the immune response against tumors, as well as on the influence of tumor exosomes during acquired chemoresistance. These observations motivate the present proposal to study the effect of exosomes derived from human Breast Cancer cell lines on immune regulation and chemoresistance. Thus, the first hypothesis of this project is that the use of dendritic cell exosomes and CTL exosomes without direct contact with other immune cells may be more resistant to immunosuppressive mechanisms of the tumor microenvironment and trigger cytotoxic responses in solid tumors of Breast Cancer. The second hypothesis is that Breast Cancer after chemotherapeutic treatment induces the production of exosomes that carry specific biomarkers related to chemoresistance. Specifically, we propose to investigate the influence of exosomes derived from tumor cells, dendritic cells and CTLs on the progression of invasive or non-invasive breast tumors, cultured in 3D. We expect exosomes to play essential roles in tumor progression. This project complements our group's collaboration with Johns Hopkins University. (AU)