**5. Extracellular vesicles towards cancer immunotherapy**

An immunosuppressive molecule like PD-L1, TGF β1, FasL, TRAIL, and NKG2D ligands are carried by TD-EVs, these ligands are the most crucial mediators of tumor immune evasion and are also the feasible targets for immunotherapy [52]. PD-L1 is more expressed when the metastatic melanoma-derived exosomes are stimulated by interferon-γ, on EVs and impede the antitumor responses. When PD-L1 is expressed on the tumor cell surface, it enhances evasion of immune surveillance through interacting with the ligand, by curbing the T-cell function. EV released from metastatic melanoma brings a PD-L1 which terminates the cytotoxic function of CD8+ T cells. PD-L1 indicates EVs were released from human blood, which is not a soluble form of PD-L1 and is also connected with the head and neck cancer progression. Similarly, PD-L1 isolated from EVs from the supernatant of murine or human HNSCC cell lines inhibits the infiltration of CD4+ T and CD8+ T cells into the tumor microenvironment, therefore enhancing tumor progression [53]. Along with the PD-L1 ligand, the other immunosuppressive molecules like TGFβ1 and NKG2D were also augmented in TD-EVs thereby bringing out the suppression of T-cells. Another activating receptor NKG2D is activated by NK cells and by T-cells, thereby presenting a crucial receptor for recognizing and terminating the cancer cells [54]. The NKG2D ligands are stress-induced self-proteins that can be divided by proteases and released as soluble molecules. The release of NKG2D ligands in the extracellular environment is to fine-tune the surface expression levels, constituting the immune evasion mechanism employed by cancer cells to neglect the NKG2D-ligand interfered immune response [55].

Few reports demonstrated that ovarian and melanoma TD-EVs activate NKG2D ligands and inhibit the activation of cytotoxic NK cells [56]. Activation of FASL and TRAIL on TD-EVs causes apoptosis in DCs and peripheral blood mononuclear cells (PBMCs) thereby promoting tumor progression [57]. The other inhibitory immunosuppressive proteins like COX2, CD39/CD73, PDL1, CTLA4, FASL are related to TD-EVs. Apart from the immune-suppressive character of TD-EVs, it would obstruct for greater immunotherapy effect and trigger the immune system. For instance, DCs are the foremost process of the immunity cycle, it activates the T-cell and thereby eliminate tumor cells. The surface membrane components that communicate with other immune cells, DCs derived EVs likely to be used as cell-free antitumor vaccines thereby delivering a novel and potential immunotherapy towards cancer [58]. Therefore, with the above observation, TD-EVs showed a major part in tumor immune evasion and growth are presented in **Table 2**. Hence, peptides, antigens, and other small molecules such as heat shock proteins could be designed shortly for cancer therapy.


*Extracellular Vesicles for Cancer Immunotherapy: Biomarkers and Beyond DOI: http://dx.doi.org/10.5772/intechopen.103783*

#### **Table 2.**

*Exosomes—cancer therapeutic targets.*
