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Our bodies are quite spectacular and are well-equipped to protect us from most dangers we encounter, both internal and external. The tools our bodies use to protect us against microscopic threats are collectively known as the immune system, and just like tools in a toolbox, the different types of immune cells have unique functions and these work in harmony to achieve a common goal. In most cases, our immune system is quite effective at protecting us from various dangers, including cancerous and precancerous cells. However, cancer is smart and has a plethora of mechanisms for hiding from the immune system and in some cases even getting the immune system to promote cancer growth.
But since our immune system already has most of the necessary tools for eliminating cancer, scientists have started exploring methods that allow them to manipulate it to treat cancer. This strategy is broadly termed cancer immunotherapy. Most currently available immunotherapeutics aim to increase CD8+ T cell responses, which are cytotoxic T cells that directly recognize specific antigen-expressing cancer cells and destroy them. However, the cancerous cells are able to escape these responses by selective or complete loss of the T cell-specific antigens by reducing the levels of major histocompatibility (MHC) I, the molecule which displays these antigens on the surface of cancer cells. Then, they continue to proliferate unchecked and eventually become CD8+ T cell resistant and unresponsive to these immunotherapeutics.
This makes it crucial to identify methods to counteract cancer cell immune evasion by exploring alternative immune cells or mechanisms effective at killing these CD8+ T cell-resistant cancer cells. Recent research has identified natural killer (NK) cells as the potential solution to this problem and an exciting target for the next-generation of immunotherapy. NK cells are also cytotoxic immune cells that destroy tumour cells or virus-infected cells; however, unlike CD8 T cells, these cells have both cytotoxicity activating and inhibiting receptors and require a net activation to kill tumour cells. For NK cells, the MHC I molecules and the cancer antigens (which are also self-antigens as cancer cells were once normal self-cells) act as an inhibitory signal by indicating they are not foreign and therefore not a “danger”. Therefore, the decreased MHC I levels in CD8+ T cell resistant tumour cells should have the counterproductive effect of increasing NK cell activation. Additionally, NK cells also recognize abnormally expressed ligands on tumour cells, which are molecules that cells use to signal DNA damage and other cancer-related injuries. Together, these should, in theory, shift the balance towards NK cell activation and promote the elimination of T cell resistant tumour cells.
STING-activating cyclic dinucleotides (CDNs) are an emerging class of immunotherapy molecules, which are used to stimulate CD8+ T cell response like most other currently available immunotherapies. Due to their impressive immunotherapeutic potential in preclinical studies, these molecules have already entered clinical trials. These molecules’ immunotherapeutic capacity emerges from their ability to activate the STING molecule, which is often referred to as the “master regulator of cancer-immunity cycle” as it plays a key role in the activation of both innate and adaptive immune responses . In particular, researchers have shown that STING activation can induce cell death, enhance cancer antigen presentation, and increase T cell activation and recruitment to tumor sites, thereby increasing the cytotoxic killing of tumour cells in a T-cell dependent manner.
Nicolai et al. (2020) demonstrated the impressive potential of NK cells as immunotherapy targets capable of clearing even CD8+ T cell resistant tumor cells by repurposing the STING-activating CDNs. Interestingly, they identified the NK cells as an additional target of STING-activating CDNs, suggesting that these molecules use a two-pronged approach to tackle tumor cells which could explain the increased efficacy on even CD8+ T cell resistant tumor cells relative to other currently available immunotherapeutics. They discovered this interesting phenomenon by treating CD8+ T cell resistant in vivo tumor models with STING-activating CDNs and observed an increased activation of NK cells and their antitumor response in comparison to untreated control tumor models. Additionally, they proposed that the NK cell activation was due to the increased expression of inflammatory genes and cellular damage, indicating ligands that were released due to STING activation were recognized by NK cells (Figure 2). Furthermore, this NK cell activation resulted in effective clearance of these in vivo CD8+ T cell resistant tumors. Overall, these findings are promising and suggest that NK cells could be the future of cancer immunotherapy.
Edited by Sara Musetti
Nicolai, C. J., Wolf, N., Chang, I., Kirn, G., Marcus, A., Ndubaku, C. O., McWhirter, S. M., & Raulet, D. H. (2020). NK cells mediate clearance of CD8+ T cell–resistant tumors in response to STING agonists. Science Immunology, 5(45), eaaz2738. https://doi.org/10.1126/sciimmunol.aaz2738
Paul, S., & Lal, G. (2017). The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Frontiers in Immunology, 8. https://doi.org/10.3389/fimmu.2017.01124
Wu, Y., Li, J., Jabbarzadeh Kaboli, P., Shen, J., Wu, X., Zhao, Y., Ji, H., Du, F., Zhou, Y., Wang, Y., Zhang, H., Yin, J., Wen, Q., Cho, C. H., Li, M., & Xiao, Z. (2020). Natural killer cells as a double-edged sword in cancer immunotherapy: A comprehensive review from cytokine therapy to adoptive cell immunotherapy. Pharmacological Research, 155, 104691. https://doi.org/10.1016/j.phrs.2020.104691
Zhu, Y., An, X., Zhang, X., Qiao, Y., Zheng, T., & Li, X. (2019). STING: A master regulator in the cancer-immunity cycle. Molecular Cancer, 18(1). https://doi.org/10.1186/s12943-019-1087-y
Header image credits: Juan Gaertner/Science source
Natural killer cells may mediate cancer immunotherapy. (n.d.). Chemical & Engineering News. https://cen.acs.org/biological-chemistry/cancer/Natural-killer-cells-mediate-cancer/96/i37