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Review
. 2023 Feb 15;7(1):17.
doi: 10.1038/s41698-023-00356-1.

Advances in NK cell therapy for brain tumors

Jawad Fares  1   2 , Zachary B Davis  3 , Julian S Rechberger  4   5 , Stephanie A Toll  6 , Jonathan D Schwartz  7 , David J Daniels  4   5 , Jeffrey S Miller #  8 , Soumen Khatua #  9
Affiliations
Review

Advances in NK cell therapy for brain tumors

Jawad Fares et al. NPJ Precis Oncol. .

Abstract

Despite advances in treatment regimens that comprise surgery, chemotherapy, and radiation, outcome of many brain tumors remains dismal, more so when they recur. The proximity of brain tumors to delicate neural structures often precludes complete surgical resection. Toxicity and long-term side effects of systemic therapy remain a concern. Novel therapies are warranted. The field of NK cell-based cancer therapy has grown exponentially and currently constitutes a major area of immunotherapy innovation. This provides a new avenue for the treatment of cancerous lesions in the brain. In this review, we explore the mechanisms by which the brain tumor microenvironment suppresses NK cell mediated tumor control, and the methods being used to create NK cell products that subvert immune suppression. We discuss the pre-clinical studies evaluating NK cell-based immunotherapies that target several neuro-malignancies and highlight advances in molecular imaging of NK cells that allow monitoring of NK cell-based therapeutics. We review current and ongoing NK cell based clinical trials in neuro-oncology.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Mechanisms of NK cell deactivation in the brain tumor microenvironment.
Mechanisms of NK cell deactivation by cancer cells include the expression of MHC-I, PD-1, CD155, and CD73 expression on cancer cells that can inhibit NK cells. Cytokine and chemokine release, such as IL-6, IL8, IL-10, VEGF, PDGF, MMP9, IDO, adenosine, PGE2, and TGF-beta can further deactivate NK cells. Proteins expressed on NK cells, such as NKG2E and TIGIT, can lead to brain tumor progression.
Fig. 2
Fig. 2. Mechanisms of NK cell activation in the brain tumor microenvironment.
Mechanisms of NK cell activation include the secretion of IFN-γ, TNF-α, perforins, and granzyme B. Cytokines, such as IL-2 and IL-15, can also prime the NK cell immune cytotoxic effect. Protein expression of NKG2D, NKp44, CD226, ABCC3, CD16, CXCR3, and CD96 can help NK cells recognize cancer cell antigens and trigger their cytotoxic effect.
Fig. 3
Fig. 3. Preclinical approaches of NK cell therapeutics in brain tumors.
Preclinical approaches involving NK cells for the treatment of brain tumors focus on three modes of action. Tumor-mediated antigen activation includes the activation of NK cell activity by cancer cell antigen recognition. Recognition of stress antigens, expressed as a result of bortezomib treatment, can activate NK cell receptors. Expression of E-cadherin, primed by oHSV-1 G207, enhances NK cell recognition and activation of NK cells through the KLRG1 receptor. The recognition of the RAET1 antigen on cancer cells by the NKG2D receptor on NK cells can also lead to NK cell activation and cytotoxicity. Other receptors on NK cells, such as KLRK1, and KLRC2/3/4 have been reported to play a role in NK cell activation against cancer cells in the brain tumor microenvironment. Growth factors, such as IL2, IL15, and PDGFDD, promote NK cell recruitment and cytotoxicity. Inhibition of TGF-beta, using viral vectors carrying shRNA, has been shown to increase NK cell activation against brain tumor cancer cells in preclinical settings. Checkpoint inhibition and immune checkpoint blockade through antibodies against GD2, PD-L1, PD-1, and B7-H3, has been reported to enhance NK cell activity in brain tumors. Viral vectors carrying siRNA targeting PD-L1 on cancer cells or lipid nanoparticles carrying siRNAs against inhibitory checkpoints, such as Cbl-b, SHP-1, and c-Cbl, on NK cells, have also been reported to activate the NK cell immune response against brain tumor cells.
Fig. 4
Fig. 4. Adoptive CAR NK cell therapeutics in brain tumors.
Chimeric antigen receptor (CAR) approaches utilize primary NK cells (isolated from patients) or NK cell lines and their transduction with a CAR gene to produce CARs. CARs consist of an antigen-recognition domain and signaling domain that utilizes down-stream signaling adapters such as the CD16 molecule. Following expansion of the CAR NK cells ex vivo, the cells are injected back into patients with brain tumors. In vitro, CAR KHYG-1 NK cells have been used to target c-Met, FOLR1, and AXL receptors that are overexpressed in glioblastoma cell lines. In preclinical settings, anti-EGFR/EGFRvIII and anti-HER2 CAR-NK cells have also demonstrated enhanced cytotoxicity against glioblastoma cells in vitro and resulted in increased tumor control and survival in animal models. Anti-EGFR CAR NK cells further showed lytic effects in combination with oncolytic virotherapy in metastatic brain cancer.
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