Recruitment and Activation of Natural Killer Cells

Natural killer (NK) cells were the first subtype of innate lymphoid cells (ILCs) to be identified and can respond to virally infected and/or transformed cells with a variety of effector functions, chiefly cell killing and production of pro-inflammatory cytokines. NK cells play a crucial role in triggering the antitumor immune response. Despite their activity in controlling tumor growth, NK cells are susceptible to multiple immunosuppressive mechanisms that are active in the TME. The field of NK cell-based immunotherapy of cancer has reached an exciting juncture.

NK cell Dysfunction in TME

Impaired NK cell function has been well documented in both solid tumors and hematologic malignancies. Many factors can lead to dysfunctional NK cells in cancer. The TME is a major obstacle to ensuring the optimum antitumor activity of NK cells, in which immunosuppressive cells and molecules limit NK cell activity. Accumulating evidence indicates that TME produced soluble modulators that negatively regulate the maturation, proliferation, and effector function of NK cells.

Fig.1 Mechanisms of NK cell dysfunction in the TME.^1,3

• Soluble immunosuppressive molecules. Many cancer-associated soluble immunosuppressive molecules negatively affect NK cell function, including IL-10, indoleamine 2,3-dioxygenase (IDO), and prostaglandin E2 (PGE2). Transforming growth factor-β (TGF-β) impairs NK cell function directly or indirectly by cell-cell contact between NK and other cytokine-producing cells. IDO overexpression was associated with tumor progression and growth arrest of tumor-infiltrating NK cells. The production of PGE2 in the TME is adopted by tumors to selectively suppress the cytotoxicity of NK cells.
• Metabolism and its production.
• TME is known to be very poor in nutrients, such as glucose and glutamine, very important for NK cells. lead to dysfunctional NK cells in cancer. This metabolic dysfunction leads to altered gene expression, downregulation of mTORC1 and MYC signaling, and decreased rates of glycolysis and oxidative phosphorylation (OXPHOS) in NK cells. Recent evidence has been reported indicating that NK cell metabolic pathways can also be dysregulated in cancers, decreasing NK cell antitumor response.
• Lactate accumulation has been associated with reduced NK cell cytotoxicity.
• Adenosine, a purine metabolite present at high concentration in the TME, also acts by limiting the activity of protective immune infiltrates, including NK cells.
• Hypoxia downregulates the effector function of NK cells.
• NK cells may express a wide range of immune checkpoint receptors that inhibit their function, including KIRs, CD94/NKG2A, PD1, CTLA4, TIM3, TIGIT, CD96, KLRG-1, LAG3, and IL-1R8.

NK Cell-based Immunotherapy

Tumor cells themselves may affect the ability of NK cells to infiltrate the tumor mass via several mechanisms. Cells from the TME may also have suppressive activities against NK cells. Thus, efforts should be made to improve NK cell recruitment and activation in the tumor bed.

Fig.2 Examples of NK cell immunotherapies targeting NK cells and tumors.^2,3

• Enhancing NK cell activity
• Immune checkpoints inhibitors. NK cells can contribute to the efficacy of inhibitory checkpoint inhibition through direct or indirect anti-tumor immunity.
• Bi- and tri-specific killer engagers strongly activate NK cell-mediated killing of tumor target cells.
• Stimulatory cytokines. Cytokines such as IL-2, IL-15, and IL-12 alone or in combination can increase the production and release of cytolytic granule content boosting NK cell anti-tumor immunity.
• Metabolic pathway and TME targeting: TGF-β inhibitor, glycogen synthase kinase-3 (GSK3) inhibitor, fructose-1,6-bisphosphatase 1 (FAB1) inhibitor.
• Adoptive NK cell therapy.

NK cell adoptive cellular immunotherapy can provide a large number of activated NK cells and exert the antitumor effect.

• Autologous NK cells and allogeneic NK cells.
• Chimeric antigen receptor (CAR) NK cells. The CARs recognize specific antigens on target cells and help the natural propensity of NK cells to kill tumor cells based on their expression of the activating receptor.

What Can We Offer

The study of the TME has completely transformed our cancer cell-centric view of tumor biology. Many strategies focusing on improving NK cells have been attempted to reshape TME. As a leading cell therapeutics biotech that provides cell therapy-related services, Creative Biolabs has developed a series of novel platforms for enhanced CAR-NK Therapy. We provide one-stop CAR-NK therapy development services, Custom iPSC-derived NK Cell Service to satisfy your demands. If you have specific research questions or requirements, please feel free to contact us.

References

1. Melaiu, Ombretta, et al. "Influence of the tumor microenvironment on NK cell function in solid tumors." Frontiers in immunology 10 (2020): 3038.
2. Ben-Shmuel, Aviad, Guy Biber, and Mira Barda-Saad. "Unleashing natural killer cells in the tumor microenvironment–the next generation of immunotherapy?." Frontiers in immunology 11 (2020): 275.
3. Distributed under Open Access license CC BY 4.0, without modification.