Role of Natural Killer Cells in Uveal Melanoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Overview of Primary Uveal Melanoma Risk Stratification
3. Limitations to Treatment of MUM
4. NK Cells: An Introduction
5. Role of NK Cells in Primary Uveal Melanoma
5.1. NK Cell Suppression within Ocular Environment
5.2. Infiltrating Immune Cells in Primary Uveal Melanoma
5.3. NK Cell Suppression in Primary Uveal Melanoma Microenvironment
6. Circulating NK Cell Control of Uveal Melanoma Metastasis
6.1. Role of Tumor HLA Expression
6.2. NK Cell Ligand Expression on Uveal Melanoma Cells
6.3. Potential Relevance of Chromosome 6 Aberrations
7. Role of NK Cells in Uveal Melanoma Liver Metastasis
7.1. Uveal Melanoma Dormancy of Hepatic Micro-Metastasis
7.2. Evidence for Role of NK Cells in Controlling Uveal Melanoma Liver Metastasis
8. Tumor Specific Suppression of NK Cells in Uveal Melanoma Metastasis
9. Hepatic Immune Tolerance and Its Role in Suppressing NK Cell Function
10. Liver Resident NK Cells: Their Potential Immunomodulatory Role in MUM
Hepatic NK Cells: Conventional vs. Liver-Resident NK Cells
11. Future Direction
12. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Liver-Directed Therapy | Systemic Therapy |
---|---|
Embolization: chemotherapy, immunotherapy, radio-embolization, bland embolization | Consideration for clinical trial |
Ablative procedures | Immune checkpoint inhibitors |
External beam radiation therapy | Cytotoxic chemotherapy |
Surgical metastasectomy (in select cases) | Targeted therapy |
Common Human NK Inhibitory Receptors (iKIRs) and Their Corresponding Ligands | Common Human NK Activating Receptors and Their Corresponding Ligands | NK Ligands Expressed in Uveal Melanoma and Their Corresponding NK Receptors |
---|---|---|
KIR2DL1 (HLA-C2) KIR2DL2–3 (HLA-C1) KIR3DL1 (HLA-HLA-Bw4) KIR3DL2 (HLA-A*03, A*011) CD94/NKG2A/B (HLA-E) [110] | NKG2D (MIC A/B, ULBP) DNAM-1 (CD112, CD155) NCRs: NKp46, NKp44, NKp30 (Heparan Sulfate Glycosaminoglycans and others) [111,112,113,114] | HLA-A/B/C (iKIRs) HLA-E (NKG2A) ULBP1–3 (NKG2D) MIC-A/B (NKG2D) CD155, CD112 (DNAM-1) [103,116] |
Clinical Trials.Gov ID | Study Drug(s) | Mechanism of Study Agent Utilizing NK Cell Anti-Tumor Effect |
---|---|---|
NCT03841110 Phase I Advanced malignancy (Including melanoma) | FT500 Pembrolizumab Atezolizumab Nivolumab IL-2 | FT500 is an allogeneic, off the shelf, NK cell product derived from induced pluripotent stem cell (FT500 administered either as monotherapy, in combination with check point inhibitor, or in combination with check-point inhibitor and IL-2). Study drugs include fludarabine and cyclophosphamide as lympho-conditioning agents |
NCT04592653 Phase II Advanced malignancy, including cutaneous melanoma | ALKS 4230 Pembrolizumab | ALKS 4230 is an engineered fusion protein comprised of modified IL-2 designed to selectively expand anti-tumor T cells and NK cells while avoiding activation of immunosuppressive cells [181]. |
NCT04477876 Cutaneous melanoma | Anti-CD160-TM agonist antibody | Transmembrane isoform of CD160 (CD160-TM) is expressed on activated NK cells. Binding of agonist antibody to CD160-TM can promote NK cell dependent anti-tumor effect [182] |
NCT03420963 Phase I Advanced malignancy, including cutaneous melanoma | Ex-vivo expanded allogeneic NK cells | Cord Blood-derived Expanded Allogeneic NK cells are cord-blood derived, expanded ex-vivo and administered to patients after pre-treatment with etoposide and cyclophosphamide |
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Javed, A.; Milhem, M. Role of Natural Killer Cells in Uveal Melanoma. Cancers 2020, 12, 3694. https://doi.org/10.3390/cancers12123694
Javed A, Milhem M. Role of Natural Killer Cells in Uveal Melanoma. Cancers. 2020; 12(12):3694. https://doi.org/10.3390/cancers12123694
Chicago/Turabian StyleJaved, Asad, and Mohammed Milhem. 2020. "Role of Natural Killer Cells in Uveal Melanoma" Cancers 12, no. 12: 3694. https://doi.org/10.3390/cancers12123694