Cancer immunotherapy, which takes advantage of innate immune response against tumor, has recently brought paradigm shift to cancer treatment. The key concept in immunotherapy is to present cancer-specific immunogens and initiate T cell-mediated cancer immunity. It is for this reason that MVs, which are capable of conveying bioactive molecules and biological information, have received renewed attention. There is complex cross-talk among cancer cells, tumor microenvironment, and the immune system, as evident by the conflicting observations of effects of TMVs. On the one hand, it has been reported that TMVs are more immunogenic than soluble antigens in mouse models [
85] as well as human cancer cells [
86]. On the other, microvesicle signalling can enhance immunosuppressive characteristics of tumor cells, contributing to escape of immune surveillance and cancer metastasis. Mesenchymal stem cell-derived EMVs, with their capacity to migrate towards inflammatory areas including solid tumors, have been used to carry tumor RNA (RNA-lipoplexes) and provoke a strong anti-tumor immune response mediated by cytotoxic CD8
+. MVs and exosome-mimetic nanovesicles delivery of siRNA or chemotherapeutic drugs that target tumors using peptide ligands for cognate receptors on the tumor cells are discussed [
87]. In mice models, TMVs by oral vaccination route effectively access and activate mucosal epithelium, resulting in subsequent antitumor T cell responses. Oral vaccination of TMVs inhibited the growth of B16 melanoma and CT26 colon cancer, which required both T cell and DC activation. Taken up by IEC in intestinal lumen, TMVs activated NOD2 and its downstream MAPK and NF-κB, leading to chemokine releasing, including CCL2, from IECs to attract CD103
+/CD11c + DCs [
50]. Maus et al. [
88] showed that melanoma-derived MVs compromised the maturation process of DCs, the latter exhibiting significantly decreased expression of CD83, CD86, migratory chemokines MIP-1, and Th1 polarizing chemokines Flt3L and IL15. Alternatively, this immunosuppressive effect of MVs can be achieved by promoting the differentiation of myeloid cells toward myeloid-derived suppressor cells [
89], which are known to counteract anti-tumor immunity. Compared to apoptotic AML cell remnants, apoptotic blebs derived from apoptotic AML cells are preferably ingested by DCs and induce their lymph node migration capacity. Co-culturing these bleb-loaded DCs with T cells led to an increased production of IFNγ compared to co-culture with unloaded or apoptotic cell remnant-loaded DCs. Considering that LAAs are scarcely characterized for AML, and that loading DCs directly with apoptotic AML cell remnants may compromise DC functions, apoptotic blebs provide an attractive and potent LAA source for developing personalized DC-based vaccines against AML [
51]. Studies by the Rughetti group [
90,
91] revealed that microvesicle-mediated antigen transfer to DCs is of crucial importance for cross-presentation of tumor-glycosylated antigens. In particular, mucine 1 (MUC1), one of the most relevant glycoproteins associated with carcinogenesis, was cross-processed and presented to antigen-specific CD8
+ T cells when carried by MVs, while the internalized soluble form of MUC1 was retained in the endolysomal/HLA-II compartment and did not activate any T cell response. They further proposed that the controversial roles of MVs in modulating immunity are dependent upon the stage of tumor progression.
DC-derived exosomes contain series of costimulatory molecules including B7–1 (CD80), B7–2 (CD86), programmed death 1-ligand (PD-L1) and PD-L2. Rather than PD-L1 and PD-L2, therapeutic effects of IL-10 treated DC and exosomes required both B7–1 and B7–2, which play a critical role in immunosuppressive functions of both DC and exosomes, giving the growing interest in exosomes for therapeutic applications [
92]. In glioblastoma, PD-L1 was expressed on the surface of some glioblastoma-derived EVs, with the potential to directly bind to programmed death-1 (PD1). These EVs block T cell activation and proliferation in response to T cell receptor stimulation. Blocking PD1 pathway significantly reversed the EV-mediated blockade of T cell activation but only when PD-L1 was present on EVs. When glioblastoma PD-L1 was up-regulated by IFN-γ, EVs also showed some PD-L1 dependent inhibition of T cell activation [
93]. HER2-positive breast cancer cells with stable over-expressing Neuromedin U and their released EVs have increased amounts of the immunosuppressive cytokine TGFβ1 and the lymphocyte activation inhibitor PD-L1, show enhanced resistance to antibody-dependent cell cytotoxicity mediated by trastuzumab, indicating a role of Neuromedin U in enhancing immune evasion [
94]. While in malignant glioma, monocytes from naïve patient peripheral blood treatmented with glioma-derived exosomes fail to induce monocytic PD-L1 expression or alter the activation of cytotoxic T-cells, but promote immunosuppressive HLA-DR low monocytic phenotypes [
95].
Probably the most promising future for therapeutic use of MVs in cancer immunotherapy is to be administered as vaccines. In their study, Zhang et al. [
96] immunized mice with extracellular vesicles isolated from different cancer cell lines, and as a result, 50% of the microparticle-immunized mice remained tumor-free after injected tumor challenges. They further discovered that tumor-derived microvesicles confer DNA fragments to DCs, leading to type I IFN production through the cGAS/STING-mediated DNA-sensing pathway. Type I IFN, in its turn, stimulate DC’s maturation and antigen-presenting capabilities. Notably, Zhang et al. reported a much lower 12.5% tumor-free rate of exosome-immunized mice after the tumor challenges. This suggests that, although the present development of extracellular vesicle-based vaccines is largely focusing on exosomal vaccines, microparticle-based vaccines appear to be more immunogenic.
Taken together, these studies highlight the potential clinical applicability of microvesicle-based vaccines in cancer immunotherapy. In future, these vaccines are expected to be administered alongside immune checkpoint inhibitors, the currently well-established immunotherapeutic approach, to further augment anti-tumor immunity.