Alteration in the expression of cell-surface proteins is a common consequence of malignant transformation. Natural killer (NK) cells use an array of germline-encoded activating and inhibitory receptors that scan for altered protein-expression patterns, but tumor evasion of detection by the immune system is now recognized as one of the hallmarks of cancer. NK cells display rapid and potent immunity to metastasis or hematological cancers, and major efforts are now being undertaken to fully exploit NK cell anti-tumor properties in the clinic. Diverse approaches encompass the development of large-scale NK cell–expansion protocols for adoptive transfer, the establishment of a microenvironment favorable to NK cell activity, the redirection of NK cell activity against tumor cells and the release of inhibitory signals that limit NK cell function. In this Review we detail recent advances in NK cell–based immunotherapies and discuss the advantages and limitations of these strategies.
At a glance
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This study established a new expansion method for obtaining large numbers of functional NK cells from small quantities of blood. Expanded populations of autologous NK cells were safe to administer to patients with cancer, and this led to enhanced cytotoxic activity against NK cell targets.
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This study was the first to test the effect of irradiation (a necessary safety measure) on the anti-tumor activity of NK cell lines and demonstrated that irradiated NK cells expressing an anti-ErbB2 CAR protected mice against metastases.
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- Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood 123, 3855–3863 (2014).
This clinical trial report demonstrated the therapeutic benefit of eliminating Treg cells with an IL-2–diphtheria fusion protein before the infusion of haploidentical NK cells in patients with AML. This study provided evidence of the negative role of Treg cells on the population expansion of NK cells after transfer and proposed that the detection of donor NK cells 7 days after infusion could serve as a surrogate marker for a clinical response.
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This study reported the first clinical trial in which recombinant IL-15 was administered to patients with metastatic cancer, which led to the clearance of lung lesions in two patients.
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- Repression of GSK3 restores NK cell cytotoxicity in AML patients. Nat. Commun. 7, 11154 (2016).
This study identified the glycogen synthetase GSK3-β as an intrinsic inhibitor of NK cell responses in patients with AML. Small-molecule inhibitors of GSK3 increased the cytotoxicity of NK cells against AML cells and proved protective in a humanized mouse model of AML.
- Azacytidine impairs NK cell reactivity while decitabine augments NK cell responsiveness toward stimulation. Int. J. Cancer 128, 2911–2922 (2011). et al.
- Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression. J. Leukoc. Biol. 91, 321–331 (2012). et al.
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- Proteasome inhibition induces apoptosis in primary human natural killer cells and suppresses NKp46-mediated cytotoxicity. Haematologica 94, 470–478 (2009). et al.
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- Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab. Blood 108, 2648–2654 (2006). et al.
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- IL-2- or IL-15-activated NK cells enhance cetuximab-mediated activity against triple-negative breast cancer in xenografts and in breast cancer patients. Breast Cancer Res. Treat. 136, 659–671 (2012). et al.
- NK cells stimulated with IL-15 or CpG ODN enhance rituximab-dependent cellular cytotoxicity against B-cell lymphoma. Exp. Hematol. 36, 69–77 (2008). et al.
- lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin. Cancer Res. 14, 4650–4657 (2008). et al.
- Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine production. Mol. Cancer Ther. 11, 2674–2684 (2012). et al.
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This paper reported the design of a '16x133' bispecific killer-cell engager that directs NK cell cytotoxic activity against CD133-expressing cancer cells. This has important therapeutic potential given its ability to target the drug-resistant cancer stem cell population that is CD133+ in many cancers.
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- IL15 trispecific killer engagers (TriKE) make natural killer cells specific to cd33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Clin. Cancer Res. (2016).
This study reports the generation of IL-15 trispecific killer-cell engagers with stable integration of IL-15 into a bispecific antibody platform that recognizes CD16 on NK cells and CD33 on myeloid cancer cells. The IL-15 linker incorporated into this construct sustained the survival and proliferation NK cells and demonstrated antitumor activity in a leukemia xenograft model.
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This was the first report showing a positive effect of a shed NKG2D ligand on the activation of NK cells. It demonstrated that MULT1, which binds with high affinity to NKG2D, stimulated NK cells and caused tumor rejection in mice.
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- Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat. Med. 17, 700–707 (2011). et al.
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- CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells. Blood 115, 3058–3069 (2010). et al.
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This report established the synergistic effect of cetuximab (mAb to EGFR) and stimulation of CD137 in promoting the activation of human NK cells and protecting mice against tumors in various xenograft models. This work supports the development of clinical trials combining cetuximab with agonist mAb to CD137.
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References 112 and 113 reported the first clinical trial of IPH2101, the antibody to human KIRs, in elderly patients with AML and patients with relapsed or refractory multiple myeloma.
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This study defined a role for the immunoglobulin family receptor CD96 in inhibiting NK cell–mediated control of tumor metastases. Pre-clinical mouse models were used to establish the anti-metastatic activity of an antibody to CD96 as a single agent or in combination with conventional checkpoint inhibitors.
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- Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma. Int. Immunopharmacol. 29, 635–641 (2015). et al.
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- The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, 508–512 (2014).
This study highlighted the therapeutic potential of targeting the TAM–CBl-b inhibitory pathway in NK cells and demonstrated the anti-metastatic activity of newly developed small-molecule inhibitor of TAM kinase.
- CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell Rep. 4, 437–444 (2013). et al.
- CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat. Immunol. 17, 816–824 (2016).
This study identified CIS, the suppressor of IL-15 signaling in NK cells, as a potent checkpoint in NK cell activation. Deletion of CIS had a profound anti-metastastic effect in vivo, and adoptive therapy of CIS-null NK cells transferred resistance to melanoma metastasis.
- Role of chemokines in the biology of natural killer cells. Curr. Top. Microbiol. Immunol. 341, 37–58 (2010).
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- The unconventional expression of IL-15 and its role in NK cell homeostasis. Immunol. Cell Biol. 92, 210–213 (2014).
- The helix-loop-helix protein ID2 governs NK cell fate by tuning their sensitivity to interleukin-15. Immunity 44, 103–115 (2016). et al.
- The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc. Natl. Acad. Sci. USA 106, 17858–17863 (2009). et al.
- Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR. Eur. J. Immunol. 43, 2138–2150 (2013). et al.
- Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155). J. Immunol. 172, 3994–3998 (2004). , , , &
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