**5. TEX and cancer immunotherapy**

There is a controversy regarding the role of exosomes in immunotherapy due to their immunostimulatory and immunoinhibitory action. However, it is imperative that TEX is responsible for the impairment of immune response and take part in the active progression of cancer as it contains several immunoinhibitory, tumor antigens, and invasive molecules to directly or indirectly suppress the immune system. It suppresses the proliferation and differentiation of the immune cells, including the remodeling of genetic materials. For example, tumor-associated antigens (TAA) bind to the antibodies produced against the cancer cells, thus reducing its efficacy in reaching the primary cancer tissue [18]. The efficacy of trastuzumab is severely affected by the TAA cargo of TEX [3]. Also, TEX has been found to play a role in inhibiting antibody-dependent cell-mediated toxicity (ADCC), which is majorly responsible for cancer prevention and the primary activity of humanized antibodies [60]. Evidence suggests that TEX also neutralizes the beneficial effect of immunotherapies. For example, TEX carrying HER2 or other TAA lessen the potential of antibody-driven immunotherapy. The TEX are present in all body fluids, which can neutralize the therapeutic antibodies, thus blocking access to the tumor. Also, the engineered T and NK cells are susceptive to the TEX carrying immunoinhibitory ligands like FasL, which is majorly responsible for the apoptosis of the adapted T cells [22]. The relapsed case of myelogenous leukemia showed the enriched presence of exosomes with immunosuppressive cargo in the plasma. These patients also responded poorly to the adoptive NK92 therapy [61]. It was speculated that a negative immunosuppressive exosome-based signaling was behind the failure of natural killer-based adoptive cell therapy. This was later confirmed by co incubating the patient-derived exosomes with NK-92 cells, wherein function and antileukemia activity of NK-92 cells were severely affected, while the vice-versa was experienced on the blocking of immunosuppressive exosomes in ex-vivo studies. Thus, it was established that TEX interferes with the immune cells and limits the therapy's therapeutic efficacy. The new target of checkpoint inhibitors is the TEX PD-L1 to mitigate the resistance faced by the current antibody approaches [62]. It could also be used as a predictor for anti-PDL1 therapy.

Also, the Tim-3 and Galectin-9 is the upcoming checkpoint inhibitor that negatively regulates the antitumor immune response [63]. The TEX are also responsible for the variations in the PD-1/PD-L1 treatment in different patients. The low surface expressivity of PD-L1 may be the reason for the low response or resistance to

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

immunotherapy [64]. Also, there is less information on whether the exosomal PD-L1 function varies with cancer type or not. The role of exosomal PD-L1 is to be elucidated further, which may help understand the early diagnosis and better therapeutic outcomes. Exosomes usually confer resistance by manipulating the cell-cell communication in the tumor microenvironment [10]. For example, the exosomes emanating from the macrophages are responsible for the drug resistance in ovarian cancer treatment in hypoxic conditions.

Further, HER2 overexpressing exosomes were found to neutralize the effect of trastuzumab [3]. In gastric cancer cells, the miRNA-21 containing exosomes secreted by the M2 macrophages were found to inhibit the action of cisplatin [65]. The miR-NAs containing exosomes are responsible for converting the monocytes to MDSCs. It has also been shown in the breast cancer model of animals that exosomes release is responsible for developing the premetastatic niche in the lungs under the influence of chemotherapy [66, 67]. Thus, the role of TEX in the development of protumor immunity and progression of metastases is involved. Also, the immunosuppressive molecules affect the antitumor activities and maturation of immune cells. Although the dual role of TEX is studied like one is the development of metastatic niche and increasing the invasiveness of cancer cells while on the other side is helping in inducing the tumor-specific immune response for the cell lysis. Thus, the role of TEX in controlling the effectiveness of immunotherapy is an interesting area to be explored.
