Therapeutic and immunomodulatory potentials of mesenchymal stromal/stem cells and immune checkpoints related molecules.

Mesenchymal stromal/stem cells (MSCs) are used in many studies due to their therapeutic potential, including their differentiative ability and immunomodulatory properties. These cells perform their therapeutic functions by using various mechanisms, such as the production of anti-inflammatory cytokines, growth factors, direct cell-to-cell contact, extracellular vesicles (EVs) production, and mitochondrial transfer. However, mechanisms related to immune checkpoints (ICPs) and their effect on the immunomodulatory ability of MSCs are less discussed. The main function of ICPs is to prevent the initiation of unwanted responses and to regulate the immune system responses to maintain the homeostasis of these responses. ICPs are produced by various types of immune system regulatory cells, and defects in their expression and function may be associated with excessive responses that can ultimately lead to autoimmunity. Also, by expressing different types of ICPs and their ligands (ICPLs), tumor cells prevent the formation and durability of immune responses, which leads to tumors' immune escape. ICPs and ICPLs can be produced by MSCs and affect immune cell responses both through their secretion into the microenvironment or direct cell-to-cell interaction. Pre-treatment of MSCs in inflammatory conditions leads to an increase in their therapeutic potential. In addition to the effect that inflammatory environments have on the production of anti-inflammatory cytokines by MSCs, they can increase the expression of various types of ICPLs. In this review, we discuss different types of ICPLs and ICPs expressed by MSCs and their effect on their immunomodulatory and therapeutic potential.