Leukemia

The immune system is tightly regulated but plastic in humans. It has several lines of control, and its imbalance has severe consequences for our health. Epigenetics encompasses heritable biochemical changes of the chromatin that do not affect the DNA sequence [1]. Epigenetics is constituted of various levels of control, from structural changes (such as 3D chromatin arrangement) to small biochemical changes (such as DNA methylation) which affect gene expression1. In the context of immunity, epigenetics has been described to control important events for the system, such as cytotoxic cell activation or exhaustion [2]. Cytotoxic cell activation is critical for tumor clearance. To activate cytotoxicity, several interactions need to occur between the target cell and the immune cell. This group of interactions are commonly known as immune checkpoint (IC) events and determine the outcome of the synapse [3]. IC signals can be co-stimulatory or co-inhibitory, and depending on the amount of signals the immune cells receive, they will determine if the system activates or not. Several rounds of inhibitory signals may induce a senescent state or exhaustion phenotype on the cytotoxic cells [3]. One of these inhibitory markers is the poliovirus receptor (PVR, also known as CD155), which interacts mainly with the T cell immunoreceptor with Ig and ITIM domains (TIGIT) in cytotoxic cells [4]. Tumoral cells can use DNA methylation to regulate inhibition of co-stimulatory or overexpression of co-inhibitory markers [3]. Hematological malignancies present aberrant promoter methylation in several immune checkpoint genes and this dysregulation supports their tumorigenesis [5–7]. Multiple myeloma (MM) is a hematological malignancy characterized by the abnormal accumulation of plasma cells in the bone marrow. MM is notorious for its incurable nature and tendency for relapse, often becoming refractory to treatment [8]. This poses significant challenges, highlighting the urgent need for innovative therapies to enhance the prognosis of affected patients. This work aims to elucidate the epigenetic regulation in PVR, an immune checkpoint marker, and its relation to cytotoxic activation and immunotherapy sensitivity in the context of MM cells.