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Targeting the epigenetic profile of CD8+ tumor-infiltrating T cells to overcome the immunosuppressive milieu of hypoxic tumor niches

Grant number: 21/10922-9
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): March 01, 2022
Effective date (End): February 28, 2023
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Lidia Maria Rebolho Batista Arantes
Grantee:Bruna Pereira Sorroche
Supervisor: Massimiliano Mazzone
Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil
Research place: University of Leuven, Leuven (KU Leuven), Belgium  
Associated to the scholarship:19/03570-9 - Immune-checkpoint inhibitors: clinical outcome and biomarkers to predict response in Melanoma patients, BP.DR

Abstract

Among the features characterizing the tumor microenvironment (TME), oxygen shortage, namely hypoxia, constitutes a hallmark of most cancer types. It is linked to immunosuppression and associated with the dysregulation of the cellular epigenetic machinery. Interestingly, the differentiation status and functionality of CD8+ T cells are defined by their epigenetic programs. Since the absence of tumor-infiltrating cytotoxic T cells underlies an important part of the disappointing clinical results of immunotherapeutics, our aim is to focus on oxygen-influenced DNA methylation patterns affecting CD8+ T cell infiltration and activation into the (hypoxic) tumor (niches). To interrogate these epigenetic marks, a library containing RNA-guided CRISPR/Cas9 targeting the genes associated with DNA (de)methylation was designed. OT-I T cells will be transduced with this lentiviral gRNA epigenetic library, transfer to recipient mice and sorted from the tumors. Their genomic DNA will be analyzed by next-generation sequencing. Distinction will be made between (1) T cells able to infiltrate hypoxic regions vs. T cells residing in the normoxic areas, and (2) cytolytic vs. dysfunctional CD8+ T cells. In this way, it will be possible to pinpoint the genes related to DNA (de)methylation whose deletion fosters CD8+ T cell accumulation in the hypoxic tumor niches with retention of functionality. Studying the link between the DNA methylation signature of cytotoxic T cells and their ability to infiltrate the tumor will disclose a list of pathways and genes that are causative for inefficient T cell fitness within the harsh (hypoxic) TME. These results will open opportunities for follow-up research lines investigating therapeutic interventions based on the exposed genes. They will also provide possible prognostic/predictive signatures to be validated in prospective studies. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SORROCHE, BRUNA PEREIRA; TEIXEIRA, RENAN DE JESUS; PEREIRA, CAIO AUGUSTO DANTAS; SANTANA, IARA VIANA VIDIGAL; VUJANOVIC, LAZAR; VAZQUEZ, VINICIUS DE LIMA; ARANTES, LIDIA MARIA REBOLHO BATISTA. PD-L1 Tumor Expression as a Predictive Biomarker of Immune Checkpoint Inhibitors' Response and Survival in Advanced Melanoma Patients in Brazil. DIAGNOSTICS, v. 13, n. 6, p. 11-pg., . (19/03570-9, 21/04100-6, 19/07111-9, 21/10922-9)

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