Influence of HIF-1alfa on sustaining the tolerogenic profile of dendritic cells during Glioblastoma cell efferocytosis.

• Grant number: 25/02607-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2025
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Alexandra Ivo de Medeiros
• Grantee: Rainá Honório dos Reis
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Dendritic cells and macrophages are specialized phagocytes responsible for the removal of apoptotic bodies, a process known as efferocytosis, both under homeostatic conditions and in pathological contexts. Dendritic cells play a key role in the antitumor response by presenting tumor cell antigens to CD4/CD8 T lymphocytes. In the tumor microenvironment, the phagocytosis of non-immunogenic dead cells (NICD), induced by radiation and certain chemotherapeutic agents, contributes to the creation of an immunosuppressive microenvironment, thereby compromising an effective antitumor response. Previous studies have demonstrated that blocking the efferocytosis of apoptotic tumor cells using anti-phosphatidylserine (PS) antibodies results in tumor progression inhibition and the restoration of the immunogenic profile of dendritic cells. However, the systemic administration of these antibodies (anti-PS) could impair the efficient removal of dead cells under physiological conditions in various tissues, potentially predisposing individuals to autoimmune diseases. Therefore, therapeutic alternatives that preserve the efferocytosis of apoptotic tumor cells while effectively inducing an immunogenic profile in dendritic cells represent a promising treatment approach. Recent data from our research group indicate that the efferocytosis of apoptotic glioblastoma cells (GBM-ACs) by BMDCs results in the acquisition of a tolerogenic profile, characterized by the production of mediators such as IL-10, TGF-beta, and IL-6, reduced expression of MHC-II and CCR7, and increased PD-L1 levels. Additionally, the efferocytosis of GBM-ACs by BMDCs induces the expression of genes related to the glycolytic pathway, along with an increase in lactate production and Phd3, a coactivator of HIF-1alfa. Furthermore, treatment with 2-DG was able to reverse the tolerogenic profile of BMDCs during the efferocytosis of GBM-ACs. Thus, aiming to elucidate the importance of HIF-1alfa and glycolysis in sustaining the tolerogenic profile of dendritic cells, the hypothesis of this study is that the efferocytosis of apoptotic glioblastoma cells leads to the stabilization of HIF-1alfa, which supports the glycolytic pathway, promoting the generation of a tolerogenic profile characterized by reduced MHC-II and CCR7 expression and increased PD-L1 levels in dendritic cells. Accordingly, the objective of this study is to evaluate the role of HIF-1¿ in activating the glycolytic pathway that sustains the tolerogenic profile in dendritic cells during the efferocytosis of GBM-ACs.