Targeting NK-cell checkpoints for cancer immunotherapy
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.
References (104)
- et al.
Boosting vaccine efficacy the natural (killer) way
Trends Immunol
(2015) - et al.
Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population
Lancet
(2000) - et al.
Evaluation of natural killer cell defense in oral squamous cell carcinoma
Oral Oncol
(2010) Dissecting CD56dim human NK cells
Blood
(2010)- et al.
Recognition of tumors by the innate immune system and natural killer cells
Adv Immunol
(2014) - et al.
Identification of a cellular ligand for the natural cytotoxicity receptor NKp44
Blood
(2013) - et al.
Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy
Nature
(1986) - et al.
Self-tolerance of natural killer cells
Nat Rev Immunol
(2006) - et al.
NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs
Blood
(2013) - et al.
The CD94/NKG2C+ NK-cell subset on the edge of innate and adaptive immunity to human cytomegalovirus infection
Semin Immunol
(2014)
Class I HLA haplotypes form two schools that educate NK cells in different ways
Semin Immunol
Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants
Science
Anti-EGFR targeted monoclonal antibody isotype influences antitumor cellular immunity in head and neck cancer patients
Clin Cancer Res
Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism?
Br J Cancer
A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma
Haematologica
Cytokine therapy reverses NK cell anergy in MHC-deficient tumors
J Clin Invest
Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide
Haematologica
The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions
Nat Immunol
CIS is a potent checkpoint in NK cell-mediated tumor immunity
Nat Immunol
The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy
Cancer Immunol Res
Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’
Nature
Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer
J Clin Oncol
Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein
Cancer Res
Functions of natural killer cells
Nat Immunol
Up on the tightrope: natural killer cell activation and inhibition
Nat Immunol
Natural regulators: NK cells as modulators of T cell immunity
Front Immunol
In vivo natural killer cell activities revealed by natural killer cell-deficient mice
Proc Natl Acad Sci U S A
Perforin is a major contributor to NK cell control of tumor metastasis
J Immunol
NKG2D function protects the host from tumor initiation
J Exp Med
Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells
J Exp Med
Perforin dependence of natural killer cell-mediated tumor control in vivo
Eur J Immunol
T-Cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy
Cancer Discov
NK cells, tumor cell transition, and tumor progression in solid malignancies: new hints for NK-based immunotherapy?
J Immunol Res
Modulation of innate immunity in the tumor microenvironment
Cancer Immunol Immunother
Prognostic value of intratumoral natural killer cells in gastric carcinoma
Cancer
A prognostic risk model for patients with triple negative breast cancer based on stromal natural killer cells, tumor-associated macrophages and growth-arrest specific protein 6
Cancer Sci
Human CD56bright NK cells: an update
J Immunol
The DNA damage response: a common pathway in the regulation of NKG2D and DNAM-1 ligand expression in normal, infected, and cancer cells
Front Immunol
Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity
Cancer Res
NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors
Nat Med
Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors
Nat Med
The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans
J Exp Med
Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells
Immunity
Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule
J Exp Med
Accelerated tumor growth in mice deficient in DNAM-1 receptor
J Exp Med
Secretory pathways generating immunosuppressive NKG2D ligands: new targets for therapeutic intervention
Oncoimmunology
PD-1 is a marker of activation on tumor infiltrating NK cells in head and neck cancer
J Immunother Cancer
Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30
Cancer Res
Rae1 and H60 ligands of the NKG2D receptor stimulate tumor immunity
Nature
The urgent need to recover MHC class I in cancers for effective immunotherapy
Curr Opin Immunol
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2022, International ImmunopharmacologyCitation Excerpt :NK cells are cytotoxic, and rapidly kill virus-infected cancer cells [39]. NK cell numbers were related with cancer survival and clinical outcomes [40–42]. Many agents active on NK cells are under clinical investigation [43].
Natural killer cells have a synergistic anti-tumor effect in combination with chemoradiotherapy against head and neck cancer
2022, CytotherapyCitation Excerpt :NK cell–mediated cytotoxicity arises from the interaction of NK cells with various cancer cells [15]. NKG2D, a member of the natural cytotoxicity receptor family, is one of the major NK cell–activating receptors, which recognize cancer cells primarily via interaction between NKG2D on NK cells and MHC class I polypeptide-related sequence A (MICA), MHC class I polypeptide-related sequence A (MICB), and UL16 binding protein (ULBP) 1 and ULBP2 on cancer cells [16]. Lymphocyte function–associated antigen 1 (LFA-1), a member of the leukocyte integrin family, is expressed on the surface of NK cells, and it adheres to intercellular adhesion molecule (ICAM)-1, ICAM-2 and ICAM-3 on cancer cells, thereby resulting in direct release of cytotoxic granules into the cancer cells [15,17-20].