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Natural killer cells lead the charge in cancer treatment innovation

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Natural killer cells lead the charge in cancer treatment innovation

In a recent review published within the journal Nature, researchers collated available publications on natural killer (NK) cells – innate immune cells involved in recognizing and eliminating cells in distress, particularly virus-infected cells and tumors. They concentrate on reviewing ongoing preclinical and clinical research in the sector of NK therapeutics, primarily elucidating the role of NK cells in cancer immunity. They further explore the potential for bioengineering approaches to harness NK cells via the event of genetically modified NK cells, immune checkpoint inhibitors, and cell engagers.

Review: Natural killer cell therapies. Image Credit: Numstocker / Shutterstock

What are NK cells, and why should we care?

Natural killer cells (NK cells) are innate lymphoid cells (ILCs), white blood cells that destroy infected and diseased cells, like virus-infected and cancerous cells. These cells were discovered relatively recently in 2008 and are naturally produced within the bone marrow. They’ll exist in populations of as much as 2 x 1010 NK cells per individual, thereby representing 1% of all immune cells and a couple of% of all lymphocytes.

Research has revealed that in healthy humans, NK cells will be present in the liver, blood, and bone marrow, serving cytolytic and cytokine-secreting functions. Scientists have traditionally classified these immune cells into two important types based on their surface molecules – CD56 (primarily cytokine-secreting function) and CD16a (predominantly cytotoxic function). Newer RNA-based classification approaches have revealed the presence of three NK cell families:

Type 1 NK (NK1) cells correspond to the normal CD56dimCD16+ NK cells and are probably the most abundant in blood. They’re characterised by the strong expression of CD16 (FCGR3A) and cytotoxicity effector molecules (GZMA, GZMB, and PRF1). They’ve recently been discovered to sometimes express genes, including SPON2, whose biological function stays to be unraveled.

Type 2 NK (NK2) cells correspond to the normal CD56vividCD16 NK cells and are unique of their transcriptional signatures, chemokine profiles, cell surface markers, and their characteristic strong expression of TCF1 (a transcriptional factor). Type 3 NK (NK3) cells are probably the most recently discovered of those three cohorts and are characterised by CD16dimadaptiveNKG2Chigh and CD57+ cells. The relative abundance of those cohorts has been observed to differ depending on pathophysiological conditions and anatomical localization.

NK cells have the unique properties of transitioning into an ILC1-like state, allowing them to amass hypothesized antitumor functions. Combined with their ability to acknowledge cells in distress and the impressive responses of CAR T-cell therapy (modified T-cells with anti-cancer properties) and immune checkpoint inhibitors over a spectrum of malignancies, NK cells are a vital focus of future anti-cancer therapeutics research.

What are NK cells’ anti-cancer advantages?

Along with the aforementioned ILC1-like state, CAR T-cell therapy, and checkpoint inhibitory functions of NK cells, novel research goals at devising mechanisms by which the tumors can now not evade T-cells and, by extension, NK cells. Unlike other T-cell populations, NK cells aren’t restricted by antigen-specific priming.

More applicably, NK cells are able to recognizing cells in distress no matter their embryonic origin or distress trigger. NK cells are further known to supply IFNγ and similar biomolecules able to stopping metastasis by forcing malignant cells right into a state of dormancy, and FLT-3L, XCL1, and CCL5, which bolster the anti-cancer properties of dendritic cells and other lymphocytes.

“…an important distinguishing factor between T and NK cells lies in the rise in NK cell function when tumour cells downregulate MHC-I expression on the cell surface. Lack of MHC-I expression is a standard T cell immune evasion mechanism. Against this, as NK cells express inhibitory MHC-I receptors, MHC-I loss contributes to the popularity and efficient elimination of tumour cells by NK cells. Thus, several features of NK cell biology make their use an interesting and complementary to other modalities utilized in oncology, including monoclonal-antibody-based therapies, cell-based therapies or a mix of each.”

Inhibitory checkpoints

Research has discovered that the activity of NK cells will be selectively switched on and off via the usage of their cell-surface inhibitory receptors similar to NKG2A, T cell immunoglobulin, and mucin domain-containing 3 (TIM-3), lymphocyte activation gene 3 (LAG3), and T cell immuno-receptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT).

Preclinical and clinical trials are currently in progress to discover and test the efficacy of monoclonal antibodies on this selective activation process. For instance, blocking NKG2A has been shown to unleash each NK- and T-cell-mediated antitumor responses, particularly against lung cancer. Similarly, blocking the LAG3 receptor has been shown to spice up NK cell antitumor immune function; TIM-3 blocking can promote the NK-cell-mediated generalized elimination of malignant cells, while TIGIT blocking can enhance NK cell proliferation and their antitumor activities against malignant B cells.

Can NK cells be used as drug products?

A growing body of evidence suggests that NK cells can perform drug functions, especially in the sector of oncological biotherapy. Plenty of studies are currently establishing the autologous and allogenic applications of NK cells, elucidating why, despite the apparent dearth of NK cell-based commercially available drugs, this is ready to vary within the near future.

“These approaches further diverge into distinct modalities, spanning from in vitro pre-activation techniques to cutting-edge genomic editing interventions. Several cancer conditions and oncological treatments, notably chemotherapy, are known to attenuate each the abundance and the operative capability of patient’s endogenous NK cells. This depletion underscores the therapeutic rationale for adoptive NK cell transfer, a method to reinforce the efficacy and resilience of NK cells throughout the TME.”

Allogenic NK cell infusions are of particular interest given their immediate bioavailability, absence of graft-versus-host disease, and robust anti-cancer potential against various malignancies. Parallel research aimed toward enhancing NK cell performance can also be ongoing, with ex vivo conditioning and genetic engineering presenting probably the most promising avenues for NK cell optimization.

Challenges to NK cells’ clinical adoption?

The current review highlights ten challenges conventional research must overcome before NK cell therapeutics receive wider medical adoption beyond current experimental procedures. These challenges will be condensed into three important elements: 1. Improving the bioavailability of NK cells, especially on the goal tumor site, 2. Enhancing the viability and cytotoxicity of NK cells, and three. The standardization and optimization of treatment procedures using NK cells.

Conclusions

The current review explores the potential and feasibility of NK cells’ clinical applications and summarizes ongoing research on these recently discovered lymphocytes. The review reveals that despite lower than 20 years of research in the sector, NK cells are emerging as a protected, practical, and potentially widely accessible technique of clinical therapy, particularly antitumor. While challenges do exist within the adoption of NK cell therapies by mainstream medicine, studies aimed toward overcoming these challenges are already underway, bringing the long run of NK cell clinical interventions closer than ever.

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