Targeting NK-cell checkpoints for cancer immunotherapy

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Highlights

Natural Killer (NK) cells are cytotoxic lymphocytes specialized in early defense against virus-infected and transformed cells. NK-cell function is regulated by activating and inhibitory surface receptors recognizing their ligands on transformed cells. Modulation of NK numbers and/or function by a variety of agents such as cytokines and monoclonal antibodies may result in enhanced anti-tumor activity. Recombinant cytokines (i.e., IL-15 and IL-2), antibodies blocking inhibitory receptors (i.e., KIR, NKG2A and TIGIT) and agonists delivering signals via CD137, NKG2D and CD16 stand out as the most suitable opportunities. These agents can be used to potentiate NKcell- mediated antibody-dependent cellular cytotoxicity (ADCC) against antibody-coated tumor cells, offering potential for multiple combinatorial immunotherapy strategies against cancer.

Section snippets

NK cells in cancer immunosurveillance

Natural Killer (NK) cells are innate lymphocytes specialized in early defense against virus-infected and transformed cells [1]. NK cell activation is regulated by a repertoire of germ-line encoded surface receptors that recognize their ligands on the target cell surface. The integration of signals derived from adhesion molecules and activating receptors triggers the polarized secretion of cytotoxic mediators (i.e., granzyme B and perforin) as well as the production of pro-inflammatory cytokines

Activating NK cell receptors and tumor cell recognition

Major NK-cell activating receptors (NKR) involved in cancer cell recognition include NKG2D, the Natural Cytotoxicity Receptor (NCR) family comprising NKp30, NKp46 and NKp44 and the co-activating receptor/adhesion molecule DNAM-1. With the exception of NKp44, induced upon activation, activating NKRs are constitutively expressed on mature NK cells (both CD56bright and CD56dim subsets) and recognize stress-induced or self-molecules which are up-regulated or re-localized to the membrane in

Human NK receptors specific for HLA class I molecules: NK cell heterogeneity, education and missing-self recognition

Transformed cells often suffer alterations in HLA-I expression thereby becoming susceptible to NK-cell recognition [33]. NK cells display three receptor systems that enable rapid NK-cell activation against target cells displaying alterations of HLA-I expression, as originally predicted by the ‘missing self’ hypothesis [34]. Inhibitory receptors specific for HLA-I molecules include killer cell immunoglobulin-like receptors (KIRs), CD94/NKG2A specific for HLA-E, and leukocyte immunoglobulin-like

Antibody-dependent NK cell-mediated cellular cytotoxicity

CD16 (FcγRIIIA), more abundantly expressed on CD56dim NK cells, is the only receptor capable of triggering resting NK cell activation by its own [54]. Antibody-dependent cellular cytotoxicity (ADCC) is triggered following CD16 recognition of antibody-coated targets. Indeed, NK cells have been shown to partially account for the clinical effect of therapeutic antibodies (mAbs) recognizing tumor associated antigens (TAA) such as rituximab or trastuzumab [55, 56, 57]. A role for ADCC as a relevant

Targetable NK-cell checkpoints for cancer immunotherapy

Several molecular tools targeting NK-cell functional checkpoints and survival are currently under development and will be readily available in the clinic.

Concluding remarks

The development of NK cell-based cancer immunotherapy is a fast evolving field. Unleashing NK cell anti-tumor responses by harnessing surface receptors in combination with cytokines depict potentially successful immunotherapeutic strategies for cancer. Nonetheless, differences between mouse and human NK cell biology as well as recent observations in clinical trials highlight the need for further studies addressing the impact of the various molecular tools on human NK cell biology.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

AM, ML-B, PB, MCO and IM are supported by Worldwide Cancer Research Grant (15-1146) and Asociación Española contra el Cáncer AECC Foundation grant (GCB15152947MELE). Plan Estatal I+D Retos (SAF2013-49063-C2-1-R), Spanish Ministry of Economy and Competitiveness (MINECO, FEDER) to ML-B. AM and LC are supported by the training program of Asociación Española contra el Cáncer Foundation.

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