Extracellular vesicle-based checkpoint regulation and immune state in cancer

Tumor cells exploit several mechanisms for hijacking an immunosuppressive tumor ecosystem in order to evade immune surveillance and to progress toward metastasis. Equipment of extracellular vesicles (EVs) with checkpoints is an example of cancer control over anti-tumor responses from immune system. Programmed death-ligand 1 (PD-L1) is a checkpoint highly expressed in a tumor at progressive stage. Interactions between PD-L1 with its receptor programmed death-1 receptor (PD-1) expressed on T cells will block the effector function of CD8+ T cells, known as one of the most important defensive cells against cancer. Evaluation of circulatory exosomal PD-L1 can be a prognostic biomarker in tumor diagnosis and responses to the immune checkpoint inhibitor (ICI) therapy, and can be considered as a tool in clinical practice for exploiting personalized therapy. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is also a checkpoint that its engagement with CD80/CD86 expressed on antigen-presenting cells (APCs), such as dendritic cells (DCs) hamper the priming phase of CD4+ and CD8+ T cells. Harvesting EVs from tumor and their modification with desired anti-checkpoint antibodies can be a promising strategy in cancer immunotherapy. The aim of this review is to discuss about EV roles in checkpoint regulation, cancer diagnosis and ICI responses, and to survey possible application of such vesicles in cancer immunotherapy.