**3. TEX and immune modulation**

The TEX are responsible for the tumor proliferation, metastasis, and antitumor response through immune and non-immune pathways. On the one hand, TEX interacts with immune cells and conveys negative signals, thereby interfering with their antitumor functions, while on the other hand, TEX promotes tumor development and facilitates tumor escape by reducing immune effector cell activity [20]. TEX transport immunoinhibitory, immunosuppressive mediators, and costimulatory molecules (like cytokines, MHC I and II, etc.) that directly or indirectly regulate immune cell formation, maturation, and antitumor activity [15, 20]. These molecules with unique cell surface motifs assist TEX in modulating the immune response, which works by the coordinated action and networking of different components. Human cancer cell exosomes may induce inter-and intracellular signals to the tumor microenvironment modulating immune cell infiltration (**Figure 2**). Recent studies show that it can suppress the immune response both in antigen-specific and non-antigen-specific fashion. For example, TEX can induce apoptosis by the transfer of FasL and TRAIL to activated T cells [22].

#### **Figure 2.**

*Role of TEX in cancer progression. TEX are responsible for transferring oncogenic proteins and nucleic acid. It can promote angiogenesis and thrombosis by activating the endothelial cells. Also, it helps in the conversion of MSCs and fibroblast to myofibroblast to promote angiogenesis and metastasis. Further, it impairs the immune response by directing apoptosis in T cells and NK cells, promoting Treg cell activity, expanding MDSC, and inhibiting DC differentiation and function. Also, it assists in developing drug resistance by delivering multidrug resistance proteins and miRNA. Moreover, it helps in neutralizing antibodies and expelling the anticancer drugs. DC: dendritic cell; MDSC: myeloid-derived suppressor cell; Treg: regulatory T cell; Breg: regulatory B cells; M2 Mϕ: M2 macrophage; NKT: natural killer T cells; NK: natural killer cells; MHC: major histocompatibility complex; TEX: tumor-derived exosomes; TGF-β: transforming growth factor-beta; IL-10: interleukin 10; TNFα: tumor necrosis factor-alpha; TNFR1: tumor necrosis factor receptor 1; TRAIL: TNF-related apoptosis-inducing ligand; TRAIL R2: TRAIL receptor 2; PGE2: prostaglandin E2; HSP: heat shock protein.*

#### *Tumor-Derived Exosome and Immune Modulation DOI: http://dx.doi.org/10.5772/intechopen.103718*

TEX include membrane-bound NKG2D ligands including MICA, MICB, or ULBP1-6, which may directly suppress NK and CD8+ T cells [23]. Also, TEX is known to suppress the expression of CD3- ζ chains in T cells to prevent their activation, and NKG2D inhibition in natural killer (NK) cells prevents NK cell-dependent toxicity [24, 25]. Tumor-derived exosomes may also suppress the anti-tumor immune response by producing prostaglandin E2 (PGE2). In the presence of TGF-β, PGE2 promotes the growth of myeloid-derived suppressor cells (MDSCs) and their suppressive function. PGE2 also inhibits NK cell cytolysis and IFN-γ production, as well as T cell IL-2 production and responsiveness [26]. TEX can also modulate the antigen-presenting cells; for example, TEX miRNA may bind to TLRs, triggering an inflammatory response. For example, miR21 and -29a secreted from exosomes of lung cancer cells bind to the human and murine TLRs and stimulate the secretion of proinflammatory cytokines like IL-6 and TNF-α [27]. TEX can also disrupt the differentiation of peripheral blood monocytes into functional dendritic cells. For example, TEX-released by colorectal and melanoma cells, for example, was shown to impede CD14+ monocyte differentiation into dendritic cells instead of causing them to highly immunosuppressive MDSCs (**Figure 2**) [25]. Tumor-derived exosomes have emerged as an important factor in the loss of antigen presenting cell function and decreased anti-tumor immune responses in patients with cancer [28].

The miRNA, HSP 70, prostaglandin E2, and TGF-β are found in the TEX and play an essential role in the differentiation of the monocytes [29]. It has been reported that the above factors can also be transported distantly by the TEX towards altering the function and differentiation of myeloid cells for favoring the MDSCs at the metastatic sites [30]. After that, MDSC induces the regulatory T cells (Treg), which play a crucial role in the tumor-suppressive microenvironment. The CD4+ T cells are directed towards the Th2 and Treg due to the expression of cytokines, TGF-β, MMPs, and growth factors in MDSCs [31]. TEX has been shown to convert the CD4+FoxP3+ T cells into Tregs via IL-10 and TGF, which are very suppressive and resistant to apoptosis [32]. Also, it has been reported that CD11b+ TEX in the tumor-bearing mice can suppress the specific response to tumor antigens via the MHC class-I independent and MHC class II-dependent pathways [33]. It suggests that TEX first stimulates the antigen-presenting cells containing CD11 in the tumor microenvironment, which then secretes the CD11b and MHC class II immunosuppressive vesicles in the circulation. Adenosine synthesis in T cells was reported to be increased by Treg coincubated with TEX, which have CD39 and CD73 ectonucleotidases [34, 35]. TEX-mediated adenosine production is implicated in suppressing activated B cells and may in-turn activate B cells into regulatory B cells (**Figure 2**).

Exosomes may promote innate and adaptive immunity, as seen in infected macrophages, which produce exosomes containing bacterial cell wall components that activate uninfected macrophages [36]. Among the adjuvants found in tumor exosomes is heat shock protein 70 (hsp70), which may stimulate anti-cancer immune responses. Researchers discovered that Hsp70/Bag-4-positive human pancreatic and colon cancer cells secrete exosomes that promote the migration and cytolytic activity of NK cells [37]. They also showed that Hsp70-positive exosomes operate in macrophage activation, as measured by TNF production [38]. Biomolecular cargo found in exosomes from DCs might facilitate the development of cell-free DC-based cancer vaccines [36, 39]. Exosomes from other cellular sources may also activate an immune response. When human alveolar epithelial cells were treated with TNF-α+ mature DC exosomes, they in turn produced inflammatory mediators such as IL-8, MCP-1, MIP-1, RANTES, and TNF-α as a result [39]. Advanced stage NSCLC or metastatic melanoma patients who received DC exosomes in phase I clinical trials showed enhanced NK cells activity [40, 41]. Injection of DC exosomes restored NKG2D levels in patients with metastatic melanoma, and tumor regression in mice was encouraged [42]. Though exosomes and TEX might induce immune activation or immunosuppression in the tumor microenvironment, but most reports for TEX suggest an immunosuppressive mode of action.
