Natural Killer Cells Could Play Key Role in Fight Against MM

Emerging research into natural killer cells has shown promise, but the findings are complicated by the heterogeneity of multiple myeloma (MM).

Multiple myeloma (MM) remains an incurable disease, but advances in our understanding of natural killer (NK) cells may provide new avenues by which to combat it.

The latest findings in NK cell research and their potential to be used in MM therapy were discussed in a new study published in Frontiers in Immunology.

Corresponding author Tony Reiman, MD, of the University of New Brunswick, and colleagues, explained that a wide array of emerging therapies, such as proteasome inhibitors, immunomodulatory drugs, and novel combination therapies, have significantly improved outcomes in patients with MM, but that the high rate of eventual relapse and the heterogeneity of the disease among patients have made it a particularly difficult cancer to fight.

“Additionally, MM is considered a disease of the immune system,” the investigators wrote. “Gradual immune dysregulation and impairment of NK cells, T cells, B cells, and dendritic cells allow malignant plasma cells to escape immunosurveillance.”

Reiman and colleagues proposed that a better understanding of the immune environment of MM could lead to strategies to reengage the immune system to inhibit MM growth. This is where NK cells potentially come into play.

These cells are considered the most active subset of innate lymphoid cells. Their name comes from their ability to target infected and malignant cells without prior sensitization. They cells have both activating and inhibitory receptors (IRs), and their activity is controlled by signals between the receptors.

One strategy for leveraging NKs is to use monoclonal antibodies to target IRs. This approach has shown benefits in other types of cancers, the authors wrote, and there is emerging evidence suggesting it is a viable option in MM as well.

They advocated paying particular attention “to understanding the heterogeneity of ligand expression both within and across patients with MM, the interplay between NK and T cells in response to IR blockade therapy, and how NK-targeted therapy can be combined with existing therapeutic options in MM patients.”

The authors said notable research has been published suggesting a role for several other IRs in MM biology: KIRs, NKG2A, TIGIT, TIM-3, PD-1, and LAG-3.

Of those, Reiman and colleagues singled out KIRs as the “most promising” target.“Not only were anti-KIR antibodies shown to be well tolerated, but they were also shown to enhance NK cell function,” they wrote.

Some of those IRs are also expressed on T cells, meaning therapies that target those receptors might boost the anticancer effects of both types of cells; however, the authors said most studies into the IRs have focused almost exclusively on T cells while ignoring NK cells.

Early failure of some clinical trials of IR blockades is likely due to intra- and interpatient heterogeneity, the authors noted. Any kind of IR-blockade therapy would likely need to be tailored to each particular patient’s expression of receptors, the investigators said, similar to what is done in solid tumors.

The investigators closed with a list of key steps they believe will need to be undertaken to bring NK-based therapy for MM close to fruition. Among those steps:

  • Profile NK cell receptors, subpopulations, cell activity, and cell function in MM
  • Profile the expression of NK cell receptor cognate ligands
  • Explore the integration of NK cell–based therapies and traditional therapies preclinically in order to optimize clinical trial design.


Alfarra H, Weir J, Grieve S, Reiman T. Targeting NK cell inhibitory receptors for precision multiple myeloma immunotherapy. Front Immunol. Published online November 12, 2020. doi:10.3389/fimmu.2020.575609