Written by: Yang, Fujian Medical University
Expert review: Professor Li Jing, Affiliated Hospital of Jiangsu University
A variety of cells in the human body can secrete exosomes, including endothelial cells, immune cells, stem cells, etc. Exosomes have anti-cancer, anti-aging, and tissue repair effects similar to those of the cells that secrete them. A recent review published in Cancer Research suggests that extracellular vesicles (i.e., exosomes) released by NK cells are very promising in the field of tumor therapy, and the proteins and microRNAs with anti-tumor effects they carry are expected to become a promising new anti-cancer method.
NK cell-derived exosomes in the treatment of cancer
NK cell-secreted exosomes have tumor homing capacity, and some studies have reported the homing capacity of NK cell-derived exosomes in a variety of tumor animal models, with exosome presence observed within tumors in minutes to hours [2]. When exosomes reach the inside of tumor tissue, they can be ingested by tumor cells, which can then kill tumor cells through a variety of mechanisms:
01
Cytotoxic effect
The exosomes secreted by NK cells contain many biologically active molecules, such as cytotoxic proteins, microRNAs, and can also carry drugs with antitumor effects. Cytotoxic proteins contained in exosomes, such as perforin, Fas/FasL, etc., can cause apoptosis of tumor cells. At the same time, microRNAs contained in exosomes can downregulate the expression of related genes, thereby inhibiting cell proliferation and inducing apoptosis of cytoma cells.
In addition, exosomes can be used as carriers for transporting antineoplastic drugs, and with their tumor targeting capabilities, the drugs can accurately reach the tumor tissue and increase the concentration of drugs inside the tumor [2]. Exosome-loaded paclitaxel shows a strong inhibitory effect on human breast cancer cells compared to the same dose of free paclitaxel[3].
02
Immunomodulatory effect
In addition to cytotoxic effects, NK cells secrete exosomes that contain a variety of immune components that can be immunomodulatory through the paracrine pathway or by targeting the immune system through the circulatory system.
At present, immunotherapy is a hot spot in cancer treatment, and the above-mentioned immunomodulatory effects of NK cell exosomes can even reverse tumor immunosuppression, making it a candidate for cancer immunotherapy.
Basic experiments have found that NK cell exosomes can stimulate immune cells, and in addition, they can also reduce the immunosuppressive effect of tumor cells, which may be related to their ability to reduce the expression of T cells indicating programmed death receptor (PD-1) [3].
The picture shows exosome cytotoxicity and immunomodulatory mechanism picture from the literature[2]
Advantages of NK cell-derived exosomes in the treatment of cancer
As early as 2002, Italian scientists first discovered that NK cell-derived exosomes can express FasL (apoptosis-related factor ligands) and perforin molecules, capable of killing several types of cancer cell lines. In addition, cytotoxicity was not observed when using NK cell-derived exosomes against normal cells[1].
Advantage one: selective lethal effect
Traditional radiotherapy for cancer treatment of radiotherapy in the removal of tumor cells at the same time will inevitably cause damage to normal cells, NK cell-derived exosomes have a selective killing effect, only attack tumor cells without damaging normal cells, is a new generation of anti-cancer strategy.
Advantage two: less side effects
Cell-based therapies, including NK cell-based infusions, are known to run the risk of triggering so-called "cytokine storms," a massive systemic release of cytokines that can force patients to pause treatment and, in some cases, even life-threatening.
However, the use of NK-derived exosomes may not be accompanied by this serious side effect, and currently, preliminary results from in vivo studies are encouraging in terms of safety [1].
Advantage three: can penetrate the "protective barrier" of cancer cells
Immune cells such as NK cells are difficult to cross the "natural barrier" in human tissues after administration, such as the blood-brain barrier and the blood-testicular barrier, so cancer cells can nest in those areas and evade immune attack. Currently, there is growing evidence that NK cell exosomes, with their nanoscale size and good tissue permeability, are able to overcome these barriers and have an advantage over using cell-based therapies [4].
Potential mechanisms by which exosomes cross the blood-brain barrier Picture from the literature[4]
Evidence from clinical studies of immune cell exosomes in the treatment of cancer
Through the review of the literature, it was found that most of the current research on immune cell exosomes in the treatment of cancer is in the animal experimental stage, and there are relatively few projects that have entered clinical trials, and the results disclosed are not much.
Image from document 5
One study found [5] that in a small group of patients with non-small cell lung cancer (NSCLC), NK cells and their exosomes, as well as circulating tumor cells (CTC), resulted in a large number of NK and NK exosomes compared to healthy donors; and the number of CTCs was negatively correlated and positively correlated with the number of NK and NK exosomes, respectively, which may be due to the increase in the number of CTCs resulting in more circulating NK cells under stress, which, coupled with the appropriate environment, may induce NK Cells actively release more exosomes. It was further demonstrated that the collected NK cell exosomes exhibited cytotoxic effects on CTC.
Thinking about the future
Talking about cancer discoloration, there is no absolutely effective treatment for cancer at present, immunotherapy is a rising star of cancer treatment in recent years, immune cells and their secretions as an important part of the immune system, occupy an important position in immunotherapy. At present, immune cell-derived exosomes have made some progress in cancer treatment, but most of them are limited to the animal research stage, and their clinical trials need to be promoted in the future.
In addition, before the clinical application of immune cell-derived exosomes, it is also necessary to unify their standards, such as preparation quality control, determination of therapeutic doses and efficacy evaluation. In short, immune cell exosomes have unique efficacy and anti-tumor activity, which makes it possible for them to become drug candidates for cancer immunotherapy, and the future can be expected!
bibliography:
[1] Fabbri M. Natural Killer Cell-Derived Vesicular miRNAs: A New Anticancer Approach?. Cancer Res. 2020;80(1):17-22.
https://pubmed.ncbi.nlm.nih.gov/31672842/
[2] Wu F, Xie M, Hun M, et al. Natural Killer Cell-Derived Extracellular Vesicles: Novel Players in Cancer Immunotherapy. Front Immunol. 2021;12:658698. Published 2021 May 21.
https://pubmed.ncbi.nlm.nih.gov/34093547/
[3] Han D, Wang K, Zhang T, Gao GC, Xu H. Natural killer cell-derived exosome-entrapped paclitaxel can enhance its anti-tumor effect. Eur Rev Med Pharmacol Sci. 2020;24(10):5703-5713.
https://pubmed.ncbi.nlm.nih.gov/32495906/
[4] Chen CC, Liu L, Ma F, et al. Elucidation of Exosome Migration across the Blood-Brain Barrier Model In Vitro. Cell Mol Bioeng. 2016;9(4):509-529.
https://pubmed.ncbi.nlm.nih.gov/28392840/
[5] Kang YT, Niu Z, Hadlock T, et al. On-Chip Biogenesis of Circulating NK Cell-Derived Exosomes in Non-Small Cell Lung Cancer Exhibits Antitumoral Activity. Adv Sci (Weinh). 2021;8( 6):2003747. Published 2021 Jan 28.
https://pubmed.ncbi.nlm.nih.gov/33747745/