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Increased immunogenicity of 5-fluorouracil-treated colorectal cancer cells by blocking autophagy with hydroxychloroquine

Grant number: 17/25660-4
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2018
Effective date (End): December 31, 2018
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Graziela Gorete Romagnoli
Grantee:Carla Sanzochi Fogolin
Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Colorectal cancer (CRC) is the third most common cancer in Brazil and worldwide. In this type of cancer, many cases of metastasis and relapsing in diseases are observed, due to the development of resistance to chemotherapeutic agents, administered at maximum tolerable doses (DMT). One of the mechanisms associated with the development of chemoresistance is autophagy, a process of self-degradation, that allows the recycling of damaged organelles and long-lived proteins, thus contributing to cell homeostasis. Autophagy works as a barrier against malignant transformation at the early stages, but pre-established tumors subvert this physiological mechanism to adapt themselves to intracellular and environmental stress. In view of this role in tumor escape, the pharmacological blockade of autophagy with hydroxychloroquine (HCQ) has been pointed out as an alternative treatment to enhance the effectiveness of chemotherapeutic agents. HCQ inhibits the fusion of the autophagosome to the lysosome, thereby preventing the formation of the autophagolysosome and its degradative pathway. Since low concentrations of chemotherapeutic agents such as paclitaxel and 5-fluorouracil (5-FU) increase the immunogenicity of tumor cells, we hypothesized that the combination of HCQ and 5-FU would lead to the blockage of autophagy, minimizing the degradation of tumor antigen in the cytosol. Preservation of antigens would increase their availability for presentation to the immune system, with reflex in the expression of activation signals in the membrane. To test this hypothesis, human dendritic cells (DCs) will be differentiated in vitro from peripheral blood monocytes of healthy donors. Immature DCs obtained at 5 days of culture will be sensitized with lysates of human colorectal cancer cells, HCT-116, previously exposed to the combination of HCQ and 5-FU. After treatment, cells will be collected and evaluated by flow cytometry for the expression of molecules involved in their ability to activate/suppress lymphocytes.

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