Training a Natural Killer!

– By Aniket Bangroo, Kirthana MV Sindhe and Subhra Prakash Chakrabarty –

Cancer is a formidable disease that may arise when some cells of our body behave in an anomalous fashion giving rise to tumors marked by abnormal growth, cell survivability and the ability to escape immune surveillance. The immune system of our body, composed of multiple cells types, attempt to keep a check on infections and the disease state, but are often unable to clear out cancer cells. Therefore, immunotherapy whereby the patient’s immune cell populations are specifically modulated to assault the cancer cells has emerged as a promising mode of cure. According to International Agency for Research on Cancer, the annual number of new cancer cases are projected to increase from 18.1 million in 2018 to 29.4 million by 2040¹. Such a very large number is possible as a large fraction of patients are non-responders to existing means of therapy. This calls for research to better the therapeutic means for targeting immune cell populations to the tumor cells to attain complete amelioration of the cancer. At Zumutor Biologics, we are focussing our scientific zeal towards innovating antibody based therapeutic tools to manipulate Natural Killer (NK) cells of our body for targeting cancer elimination.

The machinery of human immune system is armed with various cells having dedicated functions. Though research in immunotherapy has been targeted towards manipulating T cell activity, by checkpoint modulation, there is an increasing interest towards natural killer (NK) cell checkpoint modulation as well. NK cells, as part of the innate immune system, possess the ability to recognize and induce the cytotoxicity of a wide range of target cells, such as, tumour cells or virus infected cells. Apart from direct cytotoxicity, NK cells help in propagating and amplifying the immune response through the production and secretion of cytokines even without prior sensitization. The range of NK-cell responses is regulated by a balance of signalling via a wide array of surface-activating and surface-inhibitory receptors upon binding to ligands on the surface of target cells (Fig A)²

Cancer cells usually take-over this valuable response loop and exploit it to its advantage. As reported by researchers, tumor microenvironment (TME) appears to be an aggressive environment against the immune cells marked by chronic immune cell activation and inflammation, secretion of immunomodulatory cytokines, discharge of soluble factors, induction of hypoxia, and upregulation/down-regulation of inhibitory checkpoint ligands³. Studies show that NK cell features such as function, phenotype, activation, and persistence are weakened by the tumor microenvironment, leading to their dysfunction or exhaustion. Research into the mechanism of T cell dysfunction like anergy, exhaustion and senescence has led to fascinating discoveries whereby reversal of exhaustion with blocking antibodies can lead to intense clinical anti-tumor benefit^4,5. Following the same strategy, NK cells checkpoint blocking by both PD-1 and PD-L1 inhibitors, will allow manipulation into mechanisms of anergy, depletion and senescence of NK cells, therefore comprehending their complex biology in the TME⁶.

Research is targeted towards developing strategies for improving the persistence, activation, and cytolytic activity of NK cells using antibody-based/directed therapeutic activation or by cytokines or analogs (Fig B). Adoptive transfer of NK cells modified with chimeric antigen receptors (CAR) have shown promising results in cell based immunotherapy against tumor cells. However, the NK cell mediated anti-tumor response faces a lot of challenges, such as, the poor capacity of NK cells to arrive at the TME and changes in the NK cell activating receptors and their ligands in tumors, thereby showing a diminished therapeutic response⁷. One of the most popular and effective cell free therapeutic means is by antibodies capable of potentiating NK cell activity or by releasing inhibition on NK Cells by targeting immune checkpoint inhibitors⁸. Another modality of cell free immunotherapy derived from NK-cells have been proposed whereby extracellular vesicles secreted naturally from NK cells could be harvested and delivered to the TME.

This blog barely scratches the varied universe of NK cells in immune therapy against cancer. Different techniques are being used to exploit the innate ability of NK cells to target and destroy cancer cells. Identification of different immune check point inhibitors and use of immune stimulatory molecules along with advancement in ex vivo expansion and activation of NK cells will continue to open new vistas of treatment of this deadly disease.

References:
1. Bradley CJ, Yabroff KR, Dahman B, Feuer EJ, Mariotto A, Brown ML. Productivity costs of cancer mortality in the United States: 2000-2020. J Natl Cancer Inst. 2008;100(24):1763-1770. doi:10.1093/jnci/djn384
2. Meza Guzman LG, Keating N, Nicholson SE. Natural Killer Cells: Tumor Surveillance and Signaling. Cancers (Basel). 2020;12(4):952 doi:10.3390/cancers12040952.
3. Hu Weilei, Wang Guosheng, Huang Dongsheng, Sui Meihua, Xu Yibing. Cancer Immunotherapy Based on Natural Killer Cells: Current Progress and New Opportunities. Frontiers in Immunology. 2019 DOI=10.3389/fimmu.2019.01205.
4. Schwartz RH. T cell anergy. Annu Rev Immunol. 2003;21:305-334. doi:10.1146/annurev.immunol.21.120601.141110
5. Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 2013;25(2):214-221. doi:10.1016/j.coi.2012.12.003
6. Khan M, Arooj S, Wang H. NK Cell-Based Immune Checkpoint Inhibition. Front Immunol. 2020;11:167. doi:10.3389/fimmu.2020.00167
7. Parkhurst MR, Riley JP, Dudley ME, Rosenberg SA. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin Cancer Res. 2011;17(19):6287-6297. doi:10.1158/1078-0432.CCR-11-1347
8. Fais S. NK cell-released exosomes: Natural nanobullets against tumors. Oncoimmunology. 2013;2(1):e22337. doi:10.4161/onci.22337