Exosome-based cancer vaccine: A cutting-edge approach – Correspondence
Rajib Dhar, Bikramjit Bhattacharya, Debashmita Mandal, Arikketh Devi, Nanasaheb D. Thorat
Abstract
Dear Editor, Exosomes are the subpopulation of extracellular vesicles (EVs). It originated from, plasma membrane and involved in cellular communication. EVs transport several biologically active molecules (DNA, RNA, Protein, etc.) [1] from parental to recipient cells, and this cellular transportation leads to cellular reprogramming. Exosomes are secreted from all active cells. Cancer is the most lethal health crisis globally. In cancer tumor-derived exosomes (TDXs) are the most highlighted domain of current cancer research which identifies that TDXs influence all cancer cell hallmarks. Exosomes cargos can lead to uncontrolled cell proliferation, alteration of immune cell function, angiogenesis, metastasis (extracellular matrix remodeling, organ-specific metastasis), drug and therapeutic resistance, and cancer stem cell development [2,3]. All these cellular transformations create aggressive cancer propagation. The immune system is a complex multicellular interlink that develops the protection capability of the human body against multiple diseases. In cancer, the human body also develops a strong immune barrier, but immune cellular reprogramming breaks the immune protection against cancer. Tumor-derived exosomes (TDXs) are the major key factor involved in immune cell functional alterations during cancer [4]. Macrophages are a group of cells that belong to the innate immunity barrier and interestingly develop the link with adaptive immunity. The TDXs surface protein Anx II is associated with macrophages alteration in promoting angiogenesis and TDXs molecular cargo (miRNAs) involved in macrophages mediated premetastatic nish formation and M2 polarization in boosting up cancer development. Dendritic cells (DCs) are professional APCs (antigen presenting cells) which regulate the immune system activation. TDXs-mediated IL-6 expression down-regulates DCs proliferation. Nature killer (NK) cells are the groups of lymphocytes which are related to the anti-cancer activity. TDXs suppress cancer antigen binding receptor expression and as a result, reduce NK cells mediated anti-cancer cytotoxicity. TDXs downregulate B-cells proliferation. T cells are the key players in the adapted immune system. TDXs surface PDL-1 expression induces immune cells apoptosis [4,5]. Myeloid-Derived Suppressor Cells (MDSCs) are clusters of heterogenic cells population in the tumor microenvironment which actively participate in cancer development. TDXs associated heat shock protein 70 (HSP70) and miRNAs are lead MDSCs relating to immune suppression in cancer. Finally, TDXs mediate immune cell suppression to accelerate cancer progression. Cancer vaccine is a visionary scientific approach to dealing with worldwide cancer-related health crises. The journey of exosome-based vaccine development history is quite interrelating. The proposal was first executed in 1998 based on Dendritic cells derived exosomes. The unique potential of exosomes and their versatile active biomolecules like proteins, lipids, and miRNAs have encouraged the anti-cancer vaccine development dream. Tumor antigen-loaded exosomes are an innovative approach to cell-free vaccinations (this approach is under clinical trial and showing promising results). Educated DC-derived exosomes (co-culture DC and tumor antigen, then isolating exosomes from DCs) have been shown to result in T-cells mediated strong anti-cancer immune response development [6]. Exosome-mediated biomolecule transportation is also in an advanced stage in development in vaccine research, for example, exosome-mediated miRNA-30a delivery has been shown to inhibit lung cancer metastasis [7]. In exosome-based novel immunotherapeutic development is another domain of exosome-based cancer vaccine research. Exosomes have been shown to be a promising tool for immune-boosting molecular transportation against cancer [8]. Exosomes have some special properties (non-toxic, non-immune reactive, stable in biological systems) which make them a bright star in the cancer drug delivery research domain, and it is a more promising drug transporter compared to other existing delivery mediums. In drug delivery, exosomes associated with membrane protein and lipid have been shown to take a major participation in proper drug delivery and fusion with target cells membrane [9]. TDXs-based cancer vaccine has been shown to be the most exciting vaccine development approach (in this process TDXs promote high immune response against cancer, and it is easy to a collection of TDXs from almost all body fluids in humans) but the method is still under question because of the lack of properly reported scientific evidence on the oncogenic cargos of TDXs [10]. This method requires more investigations to better understand what happens if oncogenic cargos are released in normal cells? and what is the outcome of TDXs and the normal calls membrane molecular interaction? (it promotes cancer or inhibits cancer). Exosomes are considered as the best platform in promoting the next-generation of cancer vaccine development. Globally, several clinical trials are ongoing to investigate educated Dendrite cells (DCs) derived exosome (co-culture of DCs and tumor antigen and isolation of exosomes) against lung cancer (an ongoing phage 2 study) [7]. Exosomes and granulocyte-macrophage colony stimulation factor (GM-CSF) in combing the development of strong Tc (cytotoxic T-cells) mediated anti-cancer response in colon cancer (Phage-1) [9]. The MD Anderson Cancer Centre is conducting a clinical trial based on mesenchymal stem cells with KrasG12D siRNA (iExosomes) to test the efficacy against metastasis pancreatic cancer [6]. There are studies on monocytes develop dendritic cells derived exosomes and the MAGE-3 peptide (skin cancer antigen) loading approach in activating specific T cells and NK cells response against melanoma (skin cancer) [11,12]. Plant-derived exosome is another unexplored domain of exosome research. Current development of this domain indicates that this exosome has the potential on anticancer activity, and it can inhibit post-cancer treatment complication development (clinical trials have been conducted on that graves derived exosomes, it prevent chemoresistance development in oral cancer) [13]. Thus, worldwide large-scale scientific research investigation groups are currently engaged to develop efficient and affordable therapeutics based on exosomes. Exosomes are a new platform for vaccine development for cancer. This domain of research has some limitations including exosome heterogenicity, problems arising from large-scale production for clinical trials, and detail molecular understanding is required. Exosome research has opened a new door for the efficient and affordable Vaccine development platform and hopes that in the coming future it turns out to be a bright star of cancer precision medicine. Provenance and peer review Not commissioned, internally peer-reviewed. Rajib Dhar Bikramjit Bhattacharya Debashmita Mandal Arikketh Devi Nanasaheb D. Thorat 1Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, TamilNadu, 603203, India 2Department of Applied Microbiology, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India 3Department of Biotechnology, Maulana Abul Kalam Azad University of Technology (MAKAUT), Haringhata, Nadia, 741249, West Bengal, India 5Nuffield Department of Women's & Reproductive Health, Division of Medical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom E-mail addresses:[email protected]; [email protected]; [email protected]; [email protected]; [email protected]