Natural Killer Cells in Brain Tumor Research

Natural Killer (NK) cells are a type of immune cell that plays a crucial role in the body's defense against viruses and cancer. Natural killer cells are lymphocytes belonging to the same family as B cells and T cells. They are excellent at recognizing 'bad' cells (Wu 2020).

When NK cells find a harmful cell, they release special proteins called granzymes (perforins and enzymes) that poke holes in the outer layer of the targeted bad cells, causing them to break apart and die.

At first, perforins create pores, or holes, in the outer membrane of the target cell. Once these pores are formed, granzymes enter the infected or cancerous cell and induce a process that leads to cell death, effectively destroying the harmful cell. This mechanism is crucial in the immune system's defense against infections and cancer.

 

Unlike some other immune cells which require specific antigens to recognize and attack harmful cells, NK cells do not depend on prior exposure to antigens. T cells for example, are immune cells that need to be activated by recognizing specific antigens presented by antigen-presenting cells, whereas NK cells can identify and attack the same cells without the need for such prior sensitization.

This unique characteristic makes NK cells a safer alternative to T cells and extremely valuable in cancer immunotherapy, in targeting tumors that might be difficult for other treatments to reach.

 

CAR-NK Therapy for Brain Tumors

For brain tumors such as gliomas and glioblastomas, conventional therapies such as CAR T cells provide limited benefit to patients despite efforts to overcome many obstacles including physical barriers to drug delivery (e.g. blood-brain barrier, BBB). CAR T cells show limited efficacy due to tumor antigens heterogeneity, difficulty trafficking from blood to tumor sites, and overcoming the immunosuppressive composition of the tumor microenvironment (Lin 2022; Maggs 2021).

As CAR T cell therapy continues to advance, CAR NK cell therapy has also gained attention as a potential tool for cancer immunotherapy.

In glioblastoma, NK cells can mediate tumor cell killing and are associated with good prognosis (Yu 2021). A notable advantage of CAR NK cell therapy is the ability to be administered to an HLA-mismatched patient, thus allowing the possibility of an off-the-shelf therapy.

 

 

Fig.1 Interplay between cancer cells and NK cells during tumorigenesis (image from Wu et al. 2020).

 

 

Allogeneic Use of NK cells

To overcome CAR T cell therapy issues, natural killer (NK) cells are being explored as an alternative cell source for allogeneic cell therapies (which means relying on a single source of cells to treat many patients). NK cells can be obtained from blood or cord blood or be derived from hematopoietic stem and progenitor cells or induced pluripotent stem cells, and can be expanded and cryopreserved for off-the-shelf availability. 

This is advantageous because it allows for the development of "off-the-shelf" therapies, where standardized NK cells from donors can be used without the need for personalized cell preparation. Current clinical studies have demonstrated the safety and efficacy of allogeneic NK cell adoptive transfer therapies as a means for the treatment of hematologic malignancies and, to a lesser extent, solid tumors (Berrien-Elliott, 2023).

To ensure that a sufficient number of functional NK cells can be generated for therapeutic use, improving the methods of expanding and producing NK cells is a current focus of research. For example, researchers have made advancements in expanding NK cells derived from induced pluripotent stem cells (iPSCs) in large quantities, providing a potentially scalable and standardized source for therapies (Goldenson BH, 2022).

Fig.2 Lymphocyte development. Natural killer cells are lymphocytes belonging to the same family as B cells and T cells. 

Primary Antibodies Targeting NK Cells

A variety of primary antibodies are available to study NK cells and their interactions with brain tumors. Some common antibodies used in immunological research related to NK cells include:

CD56 (NCAM): CD56 is a marker of NK cells. Antibodies targeting CD56 are commonly used to identify and isolate NK cells.

• PrecisA Monoclonal Anti-NCAM1 antibody (AMAb91807)
• Triple A Polyclonal Anti-NCAM1 antibody (HPA039835)

CD16 (FcγRIIIa): CD16 is an important receptor on NK cells involved in antibody-dependent cell-mediated cytotoxicity (ADCC). Antibodies targeting CD16 are used to study this process.

• Triple A Polyclonal Anti-FCGR3A antibody (HPA055431)

CD57 (HNK-1): CD57 is another marker found on a subset of NK cells. Studying CD57 expression helps researchers understand NK cell differentiation and function.

• PrecisA Monoclonal Anti-B3GAT1 antibodies (AMAb91575, AMAb91576)
• Triple A Polyclonal Anti-B3GAT1 antibody (HPA069468)

NKG2D: NKG2D is a key activating receptor on NK cells. Antibodies targeting NKG2D are used to study the recognition of stressed or infected cells by NK cells.

KIR (Killer Immunoglobulin-like Receptors): KIRs are receptors found on NK cells that regulate their activity. Antibodies targeting KIRs are used to understand NK cell function in various contexts, including cancer immunotherapy.

CD94/KLRD1: CD94/KLRD1 is an activating receptor on NK cells. Antibodies targeting this receptor are used to study NK cell activation and function.

• Triple A Polyclonal Anti-KLRD1 antibody (HPA069688)

NKp46 (NCR1): NKp46 is a natural cytotoxicity receptor on NK cells. Antibodies targeting NKp46 are used to investigate NK cell activation and cytotoxicity.

CD314 (NKG2D ligand): CD314 is a ligand for the NKG2D receptor on NK cells. Antibodies targeting CD314 are used to study the interaction between NK cells and target cells expressing NKG2D ligands.

 

Download the Whitepaper: Glioma Markers

 

Conclusions

The use of Natural Killer (NK) cells, in treating human brain cancers has seen significant progress. NK cell therapies, in combination with other immunotherapies or treatments, hold promise for enhancing the body's natural defenses against brain tumors. Clinical trials and research initiatives are now exploring various strategies to harness the potential of NK cells in this context

 

References

Berrien-Elliott MM, Jacobs MT, Fehniger TA. Allogeneic natural killer cell therapy. Blood. 2023 Feb 23;141(8):856-868.

Goldenson BH, Hor P, Kaufman DS. iPSC-Derived Natural Killer Cell Therapies - Expansion and Targeting. Front Immunol. 2022 Feb 3;13:841107.

Lin YJ, Mashouf LA, Lim M. CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future. Front Immunol. 2022 Feb 21;13:817296.

Maggs L, Cattaneo G, Dal AE, Moghaddam AS, Ferrone S. CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma. Front Neurosci. 2021 May 25;15:662064.

Yu MW, Quail DF. Immunotherapy for Glioblastoma: Current Progress and Challenges. Front Immunol. 2021 May 13;12:676301.

Wu SY, Fu T, Jiang YZ, Shao ZM. Natural killer cells in cancer biology and therapy. Mol Cancer. 2020 Aug 6;19(1):120.