Natural killer cells lead the charge in cancer treatment innovation

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.Feb 22 2024

In a recent review published in 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 focus on reviewing ongoing preclinical and clinical research in the field 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 development 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 in the bone marrow. They can exist in populations of up to 2 x 10¹⁰ NK cells per individual, thereby representing 1% of all immune cells and 2% of all lymphocytes.

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

Type 1 NK (NK1) cells correspond to the traditional CD56^dimCD16⁺ NK cells and are the most abundant in blood. They are characterized by the strong expression of CD16 (FCGR3A) and cytotoxicity effector molecules (GZMA, GZMB, and PRF1). They have recently been discovered to sometimes express genes, including SPON2, whose biological function remains to be unraveled.

Type 2 NK (NK2) cells correspond to the traditional CD56^brightCD16^- NK cells and are unique in their transcriptional signatures, chemokine profiles, cell surface markers, and their characteristic strong expression of TCF1 (a transcriptional factor). Type 3 NK (NK3) cells are the most recently discovered of these three cohorts and are characterized by CD16^dimadaptiveNKG2C^high and CD57⁺ cells. The relative abundance of these cohorts has been observed to vary depending on pathophysiological conditions and anatomical localization.

NK cells have the unique properties of transitioning into an ILC1-like state, allowing them to acquire hypothesized antitumor functions. Combined with their ability to recognize 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 crucial focus of future anti-cancer therapeutics research.

What are NK cells’ anti-cancer benefits?

In addition to the aforementioned ILC1-like state, CAR T-cell therapy, and checkpoint inhibitory functions of NK cells, novel research aims at devising mechanisms by which the tumors can no longer evade T-cells and, by extension, NK cells. Unlike other T-cell populations, NK cells are not restricted by antigen-specific priming.

More applicably, NK cells are capable of recognizing cells in distress irrespective of their embryonic origin or distress trigger. NK cells are further known to produce IFNγ and similar biomolecules capable of preventing metastasis by forcing malignant cells into a state of dormancy, and FLT-3L, XCL1, and CCL5, which bolster the anti-cancer properties of dendritic cells and other lymphocytes.

“…a very important distinguishing factor between T and NK cells lies in the increase in NK cell function when tumour cells downregulate MHC-I expression on the cell surface. Loss of MHC-I expression is a common T cell immune evasion mechanism. By contrast, as NK cells express inhibitory MHC-I receptors, MHC-I loss contributes to the recognition 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 used in oncology, including monoclonal-antibody-based therapies, cell-based therapies or a combination of both.”

Inhibitory checkpoints

Research has discovered that the activity of NK cells can be selectively switched on and off via the use of their cell-surface inhibitory receptors such as 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 identify and test the efficacy of monoclonal antibodies in this selective activation process. For example, blocking NKG2A has been shown to unleash both NK- and T-cell-mediated antitumor responses, particularly against lung cancer. Similarly, blocking the LAG3 receptor has been shown to boost 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 field of oncological biotherapy. A number 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 set to change in 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 both the abundance and the operative capacity of patient’s endogenous NK cells. This depletion underscores the therapeutic rationale for adoptive NK cell transfer, a strategy to enhance the efficacy and resilience of NK cells within 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 at enhancing NK cell performance is also ongoing, with ex vivo conditioning and genetic engineering presenting the most promising avenues for NK cell optimization.

Challenges to NK cells’ clinical adoption?

The present review highlights ten challenges conventional research must overcome before NK cell therapeutics receive wider medical adoption beyond current experimental procedures. These challenges can be condensed into three main aspects: 1. Improving the bioavailability of NK cells, especially at the target tumor site, 2. Enhancing the viability and cytotoxicity of NK cells, and 3. The standardization and optimization of treatment procedures using NK cells.

Conclusions

The present 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 less than two decades of research in the field, NK cells are emerging as a safe, practical, and potentially widely accessible means of clinical therapy, particularly antitumor. While challenges do exist in the adoption of NK cell therapies by mainstream medicine, studies aimed at overcoming these challenges are already underway, bringing the future of NK cell clinical interventions closer than ever.