**1. Introduction**

James E. Rothman, Randy W. Schekman, and Thomas C. Südhof pioneered and discovered the molecular principles regulating cellular cargo trafficking via extracellular vesicles and were jointly awarded the 2013 Nobel Prize in Physiology or Medicine. Since then extracellular vesicles (EVs)-mediated horizontally transport of cargo across donor to recipient cells, followed by phenotypic alterations in the latter, has aroused significant scientific attention. EVs are lipid bilayer-delimited particles spontaneously secreted practically from all kinds of cells. The EVs contain cargo, including proteins, nucleic acids, lipids, metabolites, and even organelles,

representing the parent cell's physiological state [1–3]. The terminology and classification of EVs are still emerging. Exosomes are a subgroup of EVs with a size ranging from 30 to 150 nm, produced via the parent cell's endocytic pathway and engaged in intracellular communication. Exosomes are released from cells upon fusion of an intermediate endocytic compartment, multi-vesicular body (MVB), and plasma membrane. This process delivers intraluminal vesicles (ILVs) into the extracellular milieu and in circulation (**Figure 1**) [1, 2].

The conventional exosome secretion process involves a few key steps: ILVs formation and exosome biosynthesis within MVBs, MVB trafficking, and fusion with the parent cell's plasma membrane followed by released via exocytosis (**Figure 1**). Once the exosomes reach a recipient cell, they either engage with the recipient cell's surface molecules to promote juxtracrine downstream signaling, undergo fusion with the recipient cell's membrane to deposit their payloads into the cytosol, or are taken by the recipient cells via processes like phagocytosis, macropinocytosis, and receptormediated endocytosis [1, 2, 4]. The fate of internalized EVs is still poorly understood and may be determined by exosomal heterogeneity and mode of cellular uptake. Internalized exosomes go to the early endocytic pathway after being endocytosed. Early endosomal membrane fusion may deliver the soluble cargo into the cytoplasm; in contrast, EV-associated membrane proteins undergo retrograde transport to the trans-Golgi network. Endosomal recycling may deliver them to the plasma membrane or be degraded in the lysosomes [5–7].

#### **Figure 1.**

*Exosome biogenesis. The cytoplasmic outer layer protrudes to make up an initial secretory endosome (aka early endosome); intraluminal vesicles (ILVs) grow inwardly into the endosomal lumen constituting the multi-vesicular body (MVB). This process is known as the MVB biogenesis; these ILVs are secreted as exosomes when the MVB merges with the plasma membrane; but a few selected merges with the lysosome for degradation. The cargo of exosomes comprises of lipids, mRNA, miRNA, tRNA, lncRNA, DNA, proteins, adhesion molecules, receptors, and other functional compounds.*

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

The endosomal sorting complex required for transports (ESCRTs) machinery is pivotal for the biogenesis of MVBs and ILVs [2, 8]. Exosomes contain distinctive cargos, including DNA, messenger RNAs (mRNA), micro RNAs (miRNA), transfer RNAs (tRNA), long non-coding RNA (lncRNA), proteins, lipids, and metabolites, among other biologically active molecules. These payloads are carefully processed and packed into the exosomes. The contents vary with each type of cell and are influenced by different cellular phenotypes and metabolic states, thereby imparting differential biological functionality [7, 9]. Exosome protein composition analysis has indicated that certain proteins are exclusive to the cell and tissue of origin, while others are found in all exosomes. Among some of the reported, 9769 exosomal proteins (exocarta.org) are conserved, and some are cell type-specific, like the major histocompatibility complex (MHC) class-I and class-II, other cell surface receptors, and proteases. Exosomes include proteins associated with membrane transport and fusion (e.g., annexin, nuclear-related protein Rab family GTPase (Rab-GTPase), SNAREs, and heat shock proteins (HSPs). While exosomes also have membrane-associated proteins (Tetraspanins, ICAM, etc.), MVB-related proteins (ALIX and TSG101), and other proteins such as actin, myosin, and adhesion molecules such as integrins. Specific proteins are widely used as exosomal markers, including the tetraspanins (CD9, CD63, CD81, CD82, Tspan8, CD151), Alix, and Tsg101 [5, 8].

Exosomes also include cell-specific or conserved lipid content (like cholesterol, sphingomyelin, phosphatidylserine, and saturated fatty acids). Lipids are involved in exosome biosynthesis as well as maintaining homeostasis in recipient cells, in addition to safeguarding exosome structure. Additionally, exosomes contain a variety of RNAs that are active and can influence the transcriptome of recipient cells [10]. Exosomes contribute to maintaining cellular homeostasis and cell-to-cell communications and are secreted by cells in normal physiological and pathological settings [5, 11].

There is an unprecedented need to study the role of exosomes and TEX to understand tumor progression that can aid in cancer diagnosis, prognosis, and therapeutic interventions. Tumor cells are reported to secrete more exosomes than healthy cells, thereby inhibition of exosome production, release, and reduction of circulating level may be an effective cancer therapy approach [12, 13]. Understanding the interaction of cancer cells with the body's immune system is key to cancer immunology and immunotherapy success. Immune suppressive features exist in the tumor microenvironment, limiting responses to immune-regulated assaults on the tumor [14]. Several immune cell types get functionally specialized and activated to fight and neutralize tumor cells and tumorigenesis. On the contrary, the tumor cells either evade immune identification, or induce an immunosuppressive tumor microenvironment (TME) to thwart the immunological onslaught. The tumor cells strategically use TEX-driven immunosuppression in the TME and within the tumor [15].

Recent studies show that tumor-derived exosomes are widely generated and contain a wide range of immunosuppressive chemicals. Here the role of TEX is extremely significant in intercellular communication and TME remodeling. This remodeling has the potential to aid cancer cells in avoiding detection by the immune system. According to several studies, TEX released by tumor cells modulates tumorigenesis, metastasis, and angiogenesis and facilitates drug resistance [14–16]. For example, when tumor cells are subjected to hypoxia, they release exosomes with increased angiogenic and metastatic potential, supporting the concept that tumor cells respond to a hypoxic milieu by releasing exosomes to promote angiogenesis or allow progression of the tumor cells to a more suitable habitat [16, 17]. TEXs are implicated in regulating the bioactivities of their target cells via the transmission of their oncogenic cargo. EVs/exosomes have also been termed "oncosomes" in these circumstances, and they transport active proteins, lipids, and nucleic acids to recipient target cells and control gene expression, therefore regulating their function. These exosomes may potentially aid in the establishment of metastatic niches. The molecular basis driving immune avoidance and the development of metastatic niches is still ambiguous [9, 15, 18]. In the tumor microenvironment, TEXs are copiously secreted and transport a range of immunosuppressive molecules. Associations between TEXs and immune cells can suppress immune cell function and the anti-tumor immune system, both directly and indirectly. Thus, TEXs are currently being investigated as prospective candidates for cancer immunotherapy due to these features and the discovery that large quantities of these TEXs in cancer patients correspond with tumor load and progression of the disease [15, 18].
