CAR-NK Cells in the Treatment of Solid Tumors
Abstract
:1. Introduction
2. Production Process of CAR-NK Cells
2.1. Sources of NK Cells for CAR-NK Cell Therapy
2.2. Maximizing CAR-NK Cell Survival
2.3. Expansion and Activation
3. The Therapeutic Mechanisms of CAR-NK Cells
3.1. CAR-Independent Response
3.2. CAR-Dependent Response and CAR Constructs for NK Cells
3.3. The Advancement of Nanobodies
3.4. CAR Constructs Directed against Malignancies Originating from T Cells
4. NK Cell Modifications for Solid Tumor Treatment
4.1. Intrinsic Pathway Modifications
4.2. Combating Heterogeneity
4.3. Strategies against the Suppressive TME
4.4. Trafficking
5. Success in Hematological Malignancies
6. Preclinical Data on CAR-NK Cells in Solid Tumors
6.1. Glioblastoma
6.2. Breast Cancer
6.3. Pancreatic Cancer
6.4. Ovarian Cancer
6.5. Other Solid Tumors
7. Plausible Combination Therapies
8. Overview and Future Concepts
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Receptor | Impact on NK Cell | Ligands | Function |
---|---|---|---|
CD16 | Activating | Fc domain of IgG | ADCC initiation through the classical ITAM pathway. Its activation is sufficient to ignite cytotoxicity and cytokine production in resting NK cells, regardless of the adaptor particle. |
DNAM-1 | Activating | CD112, CD155 | Expressed on NK cells, T cells and monocytes. Its signaling promotes cellular adhesion. |
KIR | Activating/Inhibitory | HLA class I | Its impact on NK cells depends on the isoform. Inhibitory isoforms outweigh activating ones in the affinity to HLA class I ligands. |
NKG2A | Inhibitory | HLA-E | Forms complexes with CD94 and through the ITIM motif transduces inhibitory signals. Has a higher affinity to HLA-E ligands than the CD94/NKG2C complex. |
NKG2C | Activating | HLA-E | Forms complexes with CD94 and associates with DAP12 for an activating signal transduction. Has a lower affinity to HLA-E ligands than the CD94/NKG2A complex. |
NKG2D | Activating | MICA, MICB ULBP-1-6 | Expressed on the surface of NK, γδ T and CD8+ T cells. Associates with the DAP10 homodimer. Binds ligands upregulated by infected, stressed or transformed cells. |
NKp30 | Activating | HA/HS/GAGs | Member of the NCR family. Expressed constitutively on mature, resting or activated NK cells and some populations of T cells. Downregulated on memory-like NK cells. |
NKp44 | Activating | HA/HS/GAGs | Found only on activated NK cells. Associates with the DA12 homodimer for cytokine release ignition. |
NKp46 | Activating | HA/HS/GAGs | Uniquely expressed on NK cells. Member of the NCR family. Triggers cytotoxic reaction. |
PD-1 | Inhibitory | PDL-1, PDL-2 | Expressed on various immune cells. Binds to ligands present across multiple cancer types leading to NK cell exhaustion and cancer immune escape. The most abundantly expressed by mature NK cells. |
TIGIT | Inhibitory | CD112, CD113, CD155 | Expressed in NK and T cells. Among others, binds to the CD155 ligand rarely expressed on healthy cells, but found abundantly in cancer cell lines and human neoplasms. TIGIT blockade prevents NK and T cell exhaustion and tumor cell escape. |
2B4 | Activating | CD48 | Expressed on diverse immune cells beyond NK cells. Binds to CD48, widely expressed on cells of hematopoietic origin. In immature NK cells, can act as an inhibitor. |
Co-Receptor | Function in a CAR Particle | Description |
---|---|---|
CD28 | Co-stimulation | Essential for T cell activation. Improves anti-tumor activity and persistence at a low effector to target ratio. Induces IL-2 production and CD4+ T cell expansion. In CAR-T cells, induces central and effector memory phenotypes. Responsible for recruitment of Tregs limiting CAR-T activity. Not expressed in unmodified NK cells. Used as co-stimulatory receptor with CD3ζ in CAR-NK cells, gives superior results than CD3ζ.CAR alone. |
CD3ζ | Signaling | Expressed in unmodified NK and T cells. Used in both CAR-T and CAR-NK cells. Contains three ITAM motifs for signal transduction. Initiates cell killing. In dimers, transmits CD16 signal for ADCC initiation. Stimulates proliferation. |
DAP10 | Co-stimulation | An adaptor molecule. Does not have an ITAM motif, unable to transduce the signal. Expressed in unmodified T and NK cells. Interacts with activating NKG2D receptor. Involved in NK cells activation. |
DAP12 | Co-stimulation Signaling | An adaptor molecule. Has one ITAM motif. Superior signaling potential to CD3ζ. Interacts with NKG2C, NKp44, KIR receptors. Not expressed in unmodified T cells. Involved in NK cells activation. |
2B4 | Co-stimulation | Expressed in unmodified NK cells. In CAR-NK cells, induces cytokine production and invasiveness. |
4-1BB | Co-stimulation | Essential for T cell proliferation and survival. Enhances the proliferation of CD8+ and CD4+ T cells. Induces IL-2 production. Prolongs T cell division. Prolongs CAR-T cell persistence. Not expressed in unmodified NK cells. Used as co-stimulatory receptor with CD3ζ in CAR-NK cells. Gives superior results than CD3ζ.CAR alone. |
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Wrona, E.; Borowiec, M.; Potemski, P. CAR-NK Cells in the Treatment of Solid Tumors. Int. J. Mol. Sci. 2021, 22, 5899. https://doi.org/10.3390/ijms22115899
Wrona E, Borowiec M, Potemski P. CAR-NK Cells in the Treatment of Solid Tumors. International Journal of Molecular Sciences. 2021; 22(11):5899. https://doi.org/10.3390/ijms22115899
Chicago/Turabian StyleWrona, Ewa, Maciej Borowiec, and Piotr Potemski. 2021. "CAR-NK Cells in the Treatment of Solid Tumors" International Journal of Molecular Sciences 22, no. 11: 5899. https://doi.org/10.3390/ijms22115899