Investigation of metabolic profile of dendritic cells during efferocytosis of tumor apoptotic cells

Abstract

The phagocytosis of apoptotic cells (ACs), termed efferocytosis, is essential for maintaining immune tolerance and tissue homeostasis, and dendritic cells (DCs) and macrophages are the main cells involved in this process. DCs also play a fundamental role in the antitumor response through the presentation of tumor cell antigens to TCD4/TCD8 lymphocytes. Although tumor cells are resistant to cell death, conventional antitumor therapeutic strategies, such as radiation and chemotherapy, result in an intense accumulation of ACs in the tumor microenvironment (TME). The recognition and digestion of these apoptotic bodies sustain the immunosuppressive microenvironment and dampen the antitumor response. Clinical studies show that therapies with anti-phosphatidylserine antibody, capable to inhibit efferocytosis, boost antitumor response and inhibit the progression of metastatic breast and lung tumor. However, the systemic administration of these antibodies might compromise the efficient removal of apoptotic tissue cells that are generated on daily basis, which may predispose autoimmunities disorders. Therefore, therapeutic strategies that preserve tumor cell efferocytosis and are also capable to reprogram the tolerogenic phenotype of the phagocyte to an immunogenic phenotype represent a promising treatment option. The metabolic pathways orchestrate both activation and cellular function. It has been demonstrated that the efferocytosis of ACs activates the oxidative metabolism of lipids in macrophages, which, in turn, promotes an anti-inflammatory phenotype and favors tissue repair. However, nothing has been described about the metabolic profile acquired by DCs during efferocytosis of apoptotic tumor cells, and whether these metabolic pathways contributes to the generation of tolerogenic DCs and the impairment of antitumor response. Thus, the hypothesis of this study is that tumor cells submitted to different treatment strategies would become apoptotic cells. Efferocytosis of these apoptotic tumor cells by DCs in the TME would result in intracellular accumulation of lipids and other nutrients, thus leading to increased expression of PPAR-³ and activation of lipid metabolism and oxidative phosphorylation. The activation of these metabolic pathways would result in the activation of a tolerogenic phenotypic profile of these DCs, favoring the production of anti-inflammatory mediators, such as IL-10 and TGF-² and PGE2 that will hinder antitumor immunity. Therefore, we aimed to characterize the phenotypic and metabolic profile of DCs following efferocytosis of tumor apopotic cells. This study enables the development of an alternative antitumor therapy that will focus on the metabolic reprogramming of tolerogenic DCs following efferocytosis of apoptotic tumor cells to generate immunogenic DC and improve antitumor response. (AU)