Role of CD73 in patients with advanced melanoma treated with anti-PD-1 agents

Abstract

The treatment of metastatic melanoma was revolutionized by the approval of inhibitors of

immune-checkpoints, including antibodies targeting the programmed cell death protein 1 (PD- 1), such as nivolumab and pembrolizumab. Anti PD-1 agents improved the survival of patients

with advanced melanoma; however, a great percentage of patients do not benefit from treatment with these drugs and understanding the mechanisms influencing the response to anti PD-1 agents is an urgent need. Extracellular adenosine is a potent anti-inflammatory mediator able to impair anti-tumor immune response. The adenosine pathway has been indicated as one of the mechanisms causing immune suppression and resistance to immune-checkpoint inhibitors. The main enzyme responsible for extracellular adenosine production is the ectonucleotidase CD73, which hydrolyzes AMP into adenosine and inorganic phosphate. CD73 is anchored to the membrane of many cell types, and its expression is upregulated in several human cancers. This ectonucleotidase is also found on the membrane of exosomes, extracellular vesicles (30-150 nm) that are involved in cell-to-cell communication and are produced by almost all cell types, including cancer cells and immune cells. CD73 can be cleaved from the cell membrane and the soluble form is free to circulate in biological fluids. The main goal of this PhD project was to investigate the potential of all the forms of CD73 as predictive factors of response in patients with advanced melanoma receiving anti- PD-1 agents (nivolumab, pembrolizumab) alone or in combination with anti CTLA-4 (ipilimumab). The project was divided in four parts, each one focused on a different form of CD73: the cell-bound form expressed by circulating lymphocytes, the soluble and the exosomal form in serum and the cell-bound form within the melanoma lesion.[ ...] [edited by Author]