By Easha Vigneswaran
Cancer, one of the most difficult diseases to treat, is at the forefront of the pharmaceutical world for the development of treatments. From drugs to monoclonal antibodies, all forms of therapy are being tested with many having vast amounts of success. However, inevitably, there are also many cancers that are becoming increasingly difficult to treat and so there is an ever growing need to explore new therapeutic avenues. Whilst T and B cell immunotherapies have been widely explored, another, more intriguing immunotherapy is using natural killer (NK) cells to treat cancer. This review article aims to give a brief introduction into the huge field that is NK cell immunotherapy and to outline some of its prospects for treating cancer.
NK cells are immune cells that are part of the innate immune system and have been determined as an integral cell for tumour immunosurveillance with evidence suggesting reduced NK cell activity is associated with an increased risk of the cancer metastasising.1 Like killer T cells, these too possess cytolytic killer activity whereby upon binding to a target cell, they release cytotoxic granules like perforin and granzymes which cause cell death of the targeted cell.2 The appeal of NK cells lies in the fact they are somewhat flexible in their recognition and activation as they work via antigen independent mechanisms (unlike T cells). This therefore means they do not need prior sensitisation.3
NK cells function in a balanced manner where their ‘killing’ activity is regulated by activatory and inhibitory signals. Activatory receptors include: NKG2D which recognises stress induced ligands, FcγRIII/CD16 which binds antibodies on target cell resulting in the antibody dependent cellular cytotoxicity and NCRs that recognise a wide array of cellular ligands. Inhibitory receptors include KIRs which recognise the presence of MHC class 1 and NKG2A which recognises the presence of non-classical MHC molecules such as HLA-E. Specific target cell profiles, when recognised by the NK cell receptors will stimulate the necessary effector functions.4
It is abundantly clear there are a vast array of receptors used by NK cells that allow them to survey for cancer induced signals from stressed cells. The issue with cancer is it tends to interfere/ mask itself from immune system detection. This has been observed in colorectal cancer where NKG2D receptor levels are high during the early stages of cancer but as it progresses the receptor levels appear to decrease. This will eventually reduce the anti-tumour effects of the NK cell response.5 Another issue NK cells face when trying to kill tumour cells is that it is quite difficult for them to penetrate solid tumours which is one limitation that hinders the success of cancer immunotherapy.6 There is also evidence that the tumour micro-environment that forms to attack cancerous cells can act as an inhibitor of the NK cell response due to the presence of other immune cells secreting NK cell inhibitory cytokines.7 These various mechanisms that inhibit the NK cell response have energised research efforts to find new ways of overcoming and optimising the anti-tumour mechanism mediated by NK cells. Some of the ways researchers have been developing NK cell immunotherapy is by using cytokines and antibodies to improve the efficacy of NK cells, deriving NK cells from iPSC or modifying NK cells to produce CAR-NK cells.5
One method to optimise NK cells for combatting cancer is by ex vivo expansion and activation otherwise known as NK cell adoptive transfer. By harvesting NK cells and using cytokines to expand, proliferate and activate them ex vivo, a higher yield of active NK cells can be obtained to increase the likelihood of them penetrating and attacking the cancer. They can then be infused back into a cancer patient to target the cancer cells in the same manner they would normally. Examples of cytokines that are used include IL-2, IL-12, IL-15, IL-18 and IL-21.2 The sources that these NK cells are taken form include peripheral blood (PBMC) and umbilical cord blood. Although there have been some successful cases of NK cell adoptive transfer, there is still limited evidence pertaining to NK cell survival in vivo. For NK cells to continue to proliferate once transferred, they need a constant supply of IL-2 and IL-15. However, due to the systemic effects of cytokine therapy, they could become extremely toxic to the patient under long term treatment. This in addition to issues with maintaining a proliferative NK cell population in vivo has limited the success of adoptive NK cell therapy within clinical trials.8
Another method which is based on its famous counterpart, CAR-T cell therapy, CAR-NK therapy follows a similar principle of genetically modifying the NK cells to express chimeric antigen receptors (CARs). These are receptors are designed to recognise a specific type of antigen expressed on the target cell, in this case a tumour cell.1 The type of antigen recognised can be designed to be specific cancer antigen: CS1 expressed in myeloma cells; HER2 expressed on breast, colon and ovarian cancer cells and EGFR expressed in glioblastomas. If ligand binding occurs between the CAR and tumour antigen, an immune synapse can form to allow directed release of cytotoxic granules into the tumour cells thus causing cell death.9
In addition to the CAR dependent mechanism, NK cells have an intrinsic ability to target cancer cells due to the presence of their KIR receptors. One hallmark of cancer cells is that cancer cells can evade the immune system via a mechanism that downregulates the presentation of MHC I molecules. Whilst this prevents a cytotoxic T cell response, it has the opposite effect on NK cells. KIRs on the NK cell rely on the presence of MHC to induce the inhibitory response. However, if no ligand binding occurs between the NK cell and cancer cell, the inhibitory response is not stimulated. This results in the the activatory response continuing, thus increasing the killing activity. This ultimately results in death of the cancer cell.10
Currently there are numerous NK cell cancer immunotherapy clinical trials that are at various stages. The possibility that these treatments become viable options for cancer treatment is contingent on the success of these trials. It remains evident there are still a variety of issues that hinder the performance of NK cell immunotherapy. However, when considering the vast improvements that have been made in bioscience research, it is inevitable that similar improvements can be made in this field to add to the ever-growing treatment options for cancer patients.
- Liu S, Galat V, Galat4 Y, Lee YKA, Wainwright D, Wu J. NK cell-based cancer immunotherapy: from basic biology to clinical development. Journal of Hematology & Oncology. 2021;14(1): 7. https://doi.org/10.1186/s13045-020-01014-w.
- Paul S, Lal G. The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy. Frontiers in Immunology. 2017;8: 1124. https://doi.org/10.3389/fimmu.2017.01124.
- Bald T, Krummel MF, Smyth MJ, Barry KC. The NK cell-cancer cycle: advances and new challenges in NK cell-based immunotherapies. Nature Immunology. 2020;21(8): 835–847. https://doi.org/10.1038/s41590-020-0728-z.
- Shaver KA, Croom-Perez TJ, Copik AJ. Natural Killer Cells: The Linchpin for Successful Cancer Immunotherapy. Frontiers in Immunology. 2021;12: 679117. https://doi.org/10.3389/fimmu.2021.679117.
- Hu W, Wang G, Huang D, Sui M, Xu Y. Cancer Immunotherapy Based on Natural Killer Cells: Current Progress and New Opportunities. Frontiers in Immunology. 2019;10: 1205. https://doi.org/10.3389/fimmu.2019.01205.
- Zhang C, Hu Y, Shi C. Targeting Natural Killer Cells for Tumor Immunotherapy. Frontiers in Immunology. 2020;11: 60. https://doi.org/10.3389/fimmu.2020.00060.
- Wu SY, Fu T, Jiang YZ, Shao ZM. Natural killer cells in cancer biology and therapy. Molecular Cancer. 2020;19(1): 120. https://doi.org/10.1186/s12943-020-01238-x.
- Vahedi F, Nham T, Poznanski SM, Chew MV, Shenouda MM, Lee D, et al. Ex Vivo Expanded Human NK Cells Survive and Proliferate in Humanized Mice with Autologous Human Immune Cells. Scientific Reports. 2017;7(1): 12083. https://doi.org/10.1038/s41598-017-12223-8.
- Yilmaz A, Cui H, Caligiuri MA, Yu J. Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy. Journal of Hematology & Oncology. 2020;13(1): 168. https://doi.org/10.1186/s13045-020-00998-9.
- Albinger N, Hartmann J, Ullrich E. Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany. Gene Therapy. 2021;28(9): 513–527. https://doi.org/10.1038/s41434-021-00246-w.