Extracellular Vesicles in Oncology: from Immune Suppression to Immunotherapy

Abstract

Exosomes are involved in cell-to-cell communication and play a crucial role in cellular physiology. The role of exosomes in cancer has been widely explored. Tumor cells have evolved and adapted to evade the immune response. The study of the immune system's modulations in favor of rogue tumor cells led to the development of a novel immunotherapeutic strategy targeting the immune checkpoint proteins (ICPs). In clinical settings, the response to ICP therapy has been inconsistent and is difficult to predict. Quantitating the targeted ICPs through immunohistochemistry is one approach, but is not pragmatic in a clinical setting and is often not sensitive. Examining the molecules present in bodily fluids to determine ICP treatment response, "liquid biopsy" is a convenient alternative. The term "liquid biopsy" refers to circulating tumor cells (CTCs), extracellular vesicles (EVs), non-coding (nc) RNA, circulating tumor DNA (ctDNA), circulating free DNA (cfDNA), etc. EVs includes exosomes, microvesicles, and oncosomes. Herein, we focus on exosomes isolated from bodily fluids and their use in liquid biopsy. Due to their unique ability to transfer bioactive molecules and perturb the physiology of recipient cells, exosomes have garnered attention for their immune modulation role and as a resource to identify molecules associated with liquid biopsy-based diagnostic methods. In this review, we examine the putative role of exosomes and their cargo in influencing the immune system. We discuss the immune and tumor cells present in the tumor microenvironment (TME), and the exosomes derived from these cells to understand how they participate in creating the immune-suppressive TME. Additionally, use of exosomes in liquid biopsy-based methods to measure the treatment response elicited by immunotherapy is discussed. Finally, we describe how exosomes have been used to develop immune therapies, especially cell-free vaccines, for cancer treatment.

Keywords: cancer; exosomes; immunotherapy; liquid biopsy; tumor microenvironment.

Fig. 1

Exosomes from tumor cells (TEX) play an important role in modulating immune cells in the TME and promote different activities resulting in favorable condition for tumor propagation. Figure created with BioRender.com

Fig. 2

The exosomes contains various immunogenic proteins including immune checkpoint proteins. It has been hypothesized that these checkpoint proteins play crucial role in treatment outcomes. (a) Detection of PD-L1 in exosomes derived from the urine of non-small cell lung cancer (NSCLC) patients. Ant-PD-L1 antibody conjugated to gold was used to detect the presence of PD-L1 on the surface of exosomes. (b) A protein array detects twenty-three different immune checkpoint proteins on exosomes. (c) Expression analysis of immune checkpoint proteins show change in expression profile in response to the immune therapy