Elsevier

Seminars in Immunology

Volume 31, June 2017, Pages 20-29
Seminars in Immunology

Review
Natural killer cell-mediated immunosurveillance of human cancer

https://doi.org/10.1016/j.smim.2017.08.002Get rights and content

Abstract

The contribution of natural killer (NK) cells to immunosurveillance of human cancer remains debatable. Here, we discuss advances in several areas of human NK cell research, many of which support the ability of NK cells to prevent cancer development and avoid relapse following adoptive immunotherapy. We describe the molecular basis for NK cell recognition of human tumor cells and provide evidence for NK cell-mediated killing of human primary tumor cells ex vivo. Subsequently, we highlight studies demonstrating the ability of NK cells to migrate to, and reside in, the human tumor microenvironment where selection of tumor escape variants from NK cells can occur. Indirect evidence for NK cell immunosurveillance against human malignancies is provided by the reduced incidence of cancer in individuals with high levels of NK cell cytotoxicity, and the significant clinical responses observed following infusion of human NK cells into cancer patients. Finally, we describe studies showing enhanced tumor progression, or increased cancer incidence, in patients with inherited and acquired defects in cellular cytotoxicity. All these observations have in common that they, either indirectly or directly, suggest a role for NK cells in mediating immunosurveillance against human cancer. This opens up for exciting possibilities with respect to further exploring NK cells in settings of adoptive immunotherapy in human cancer.

Introduction

The concept of immunosurveillance of cancer was outlined half a century ago [1]. The general view was that tumor cell transformation is a frequent event and is under constant control by the immune system. A prediction of the concept was that genetically immunodeficient individuals, or those being treated with immunosuppressive drugs, would have a markedly increased incidence of cancer. At first, clinical observations provided only marginal support for this concept. The rate of spontaneous malignant transformation was likely overrated. However, based on data from experimental models in mice and epidemiological studies in humans [2], the concept has now gained acceptance in a wider research community. Indeed, patients with inherited or acquired immunodeficiencies, and patients on immunosuppressive drugs, have higher incidences of cancer [2]. Defects affecting T cells or other parts of the adaptive immune system have been particularly implicated in this context. However, innate constituents of the immune system, including natural killer (NK) cells, may also play a significantly important role.

NK cells were initially identified due to their ability to kill tumor cell lines in vitro [3], [4]. Since that discovery, a large number of studies has demonstrated NK cell-mediated killing of many types of tumor cell lines in vitro, and in experimental animal models [5], [6], [7]. Studies have also shown that NK cells are involved in rejection responses against experimentally induced and spontaneously developing tumors in mice [8], [9], [10]. Indirect evidence for NK cell targeting of human tumors has come from studies of allogeneic hematopoietic stem cell transplantation (HSCT), in particular haploidentical HSCT against acute myeloid leukemia (AML) [11], [12].

NK cell recognition of tumor cells is a tightly regulated process involving the interaction of specific ligands on the tumor cells with NK cell receptors and subsequent integration of signals derived from such receptors in the responding NK cells [13], [14]. The earliest insights into the molecular specificity of NK cells were based on the observation that NK cell cytotoxicity was triggered by tumor cells lacking expression of all (or certain) self-major histocompatibility complex (MHC) class I molecules, a phenomenon referred to as “missing-self” recognition [6], [15]. These observations led to the identification of specific NK cell-inhibitory receptors that recognize MHC class I molecules [16], [17] and were later followed by identification of NK cell-activating receptors, binding specific ligands expressed by tumor cells [18], [19], [20], [21], [22], [23].

Furthermore, in contrast to what was initially thought, it is now clear that NK cells are not a homogeneous set of cytotoxic lymphocytes. Rather, during the past two decades we have gained a deep understanding of this population of lymphocytes revealing significant insights into their differentiation and functional diversification [24], [25], [26], [27], [28], [29], [30], [31], [32]. The extensive diversity in the human NK cell repertoire, both within and between individuals, is known to be driven by a combination of genetic variations in receptor expression, homeostatic turnover and epigenetic reprogramming following the response to pathogenic challenges, in particular by human cytomegalovirus (CMV) [28], [31], [32], [33], [34], [35]. Much knowledge in this respect evolves from studies of NK cells in human peripheral blood. NK cells that reside in corresponding peripheral tissues including solid tumors are, however, still relatively less well-characterized [36]. In this respect, furthering our understanding of the biology of tumor-resident NK cells is essential to decipher their direct potential contribution to tumor control.

Herein, we review a series of findings relating to the complex interactions between NK cells and tumor cells. We discuss evidence for a direct role of NK cells in controlling human cancer development and/or progression, as well as studies showing enhanced cancer susceptibility and/or progression in patients with abnormal NK cell function. Together, these studies provide compelling evidence for an important role of NK cells in immunosurveillance against development and progression of cancers in humans. This concept encourages further efforts to develop new treatment options aimed at strengthening endogenous NK cell responses to tumor cells as well as designing protocols that utilize adoptive transfer of autologous and allogeneic NK cells to target human solid and hematological malignancies.

Section snippets

NK cell interactions with human tumor cells and the tumor microenvironment

NK cells can control cancers directly by interacting with tumor cells and indirectly by influencing the activities of other immune cells in the tumor microenvironment. Direct tumor cell lysis by NK cells is thought to be principally perforin-dependent, as extensively demonstrated in many experimental model systems [37]. However, NK cells can also induce tumor cell elimination through death receptor-mediated pathways such as TRAIL and FasL [38]. Further, activated NK cells produce numerous

NK cells with intact function prevent human cancer development and/or progression

In addition to the indisputable evidence for NK cell targeting of tumor cells in vitro and in vivo in mice, some intriguing clinical observations also point to the existence of NK cell-mediated immunosurveillance in human cancer. In Sections 3.1–3.3, we describe examples of studies indicating a direct role of NK cells in controlling human cancer development including a unique study in which reduction of cancer outcomes was observed on a population-based level in individuals with higher than

NK cells with inherited or acquired defects fail to prevent human cancer development and/or progression

Above, we described examples of studies indicating a direct role of NK cells in controlling human cancer development. In Section 2.3, we have discussed some aspects of tumor-induced suppression of NK cells. The latter included studies of downregulated NK cell-activation receptor expression. Many other related findings not covered in this review have focused on alterations in, e.g., the expression and function of signal-transducing proteins in tumor-associated NK cells [132], [133]. Below, in

Outlook – NK cells in the era of cancer immunotherapy

Cancer immunotherapy, including many cell-based therapies, is currently emerging as a central treatment-modality in a wide range of cancer types. It is obvious that T cell-mediated immune surveillance and recognition of neo-antigens are critical for the success of currently available checkpoint inhibitors directed against PD-1 and CTLA-4 [153]. In this review, we have outlined experimental and clinical evidence that NK cells and the innate immune system contribute to the control of malignant

Disclosure of potential conflicts of interest

K.J. Malmberg serves on the Scientific Advisory Board of Fate Therapeutics. H.G. Ljunggren serves on the Scientific Advisory Board of CellProtect Nordic Pharmaceuticals and HOPE Bio-Sciences; on the Board of Directors of Vycellix; and is a collaborator with Fate Therapeutics. The respective relationships have been reviewed and managed by Oslo University Hospital and Karolinska Institutet in accordance with the institutions’ conflict of interest policies.

Acknowledgements

The authors are supported grants from the Swedish Research Council, the Swedish Children’s Cancer Society, the Swedish Foundation for Strategic Research, the Swedish Cancer Society, the Swedish Society for Medical Research (SSMF), the Jeansson’s Foundations, Radiumhemmets Research foundation, the Knut and Alice Wallenberg Foundation, the Karolinska Institutet, the Karolinska University Hospital, the Norwegian Research Council, the Norwegian Cancer Society, the Norwegian Research Council, the

References (155)

  • H. Schlums et al.

    Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function

    Immunity

    (2015)
  • M. Guma et al.

    Imprint of human cytomegalovirus infection on the NK cell receptor repertoire

    Blood

    (2004)
  • M. Guma et al.

    Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts

    Blood

    (2006)
  • V. Screpanti et al.

    Impact of FASL-induced apoptosis in the elimination of tumor cells by NK cells

    Mol. Immunol.

    (2005)
  • C. Fauriat et al.

    Regulation of human NK-cell cytokine and chemokine production by target cell recognition

    Blood

    (2010)
  • M. Uhrberg et al.

    Human diversity in killer cell inhibitory receptor genes

    Immunity

    (1997)
  • N.M. Valiante et al.

    Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors

    Immunity

    (1997)
  • S. Andersson et al.

    KIR acquisition probabilities are independent of self-HLA class I ligands and increase with cellular KIR expression

    Blood

    (2009)
  • S. Andersson et al.

    Tolerant and diverse natural killer cell repertoires in the absence of selection

    Exp. Cell Res.

    (2010)
  • S. Diermayr et al.

    NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities

    Blood

    (2008)
  • N. Anfossi et al.

    Human NK cell education by inhibitory receptors for MHC class I

    Immunity

    (2006)
  • H. Schlums et al.

    Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

    Blood

    (2017)
  • M.A. Corat et al.

    Acquired somatic mutations in PNH reveal long-term maintenance of adaptive NK cells independent of HSPCs

    Blood

    (2017)
  • J. Yu et al.

    CD94 surface density identifies a functional intermediary between the CD56bright and CD56dim human NK-cell subsets

    Blood

    (2010)
  • M. Della Chiesa et al.

    Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus?

    Blood

    (2012)
  • B. Foley et al.

    Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function

    Blood

    (2012)
  • R. Godal et al.

    Natural killer cell killing of acute myelogenous leukemia and acute lymphoblastic leukemia blasts by killer cell immunoglobulin-like receptor-negative natural killer cells after NKG2A and LIR-1 blockade

    Biol. Blood Marrow Transplant.

    (2010)
  • D. Pende et al.

    Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Poliovirus receptor (CD155) and Nectin-2 (CD112)

    Blood

    (2005)
  • L. Ruggeri et al.

    Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation

    Blood

    (1999)
  • E. Carbone et al.

    HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells

    Blood

    (2005)
  • E. Alici et al.

    Autologous antitumor activity by NK cells expanded from myeloma patients using GMP-compliant components

    Blood

    (2008)
  • M.A. Geller et al.

    Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model

    Cytotherapy

    (2013)
  • K.J. Malmberg et al.

    Escape from immune- and nonimmune-mediated tumor surveillance

    Semin. Cancer Biol.

    (2006)
  • C. Fauriat et al.

    Deficient expression of NCR in NK cells from acute myeloid leukemia: evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction

    Blood

    (2007)
  • F.M. Burnet

    The concept of immunological surveillance

    Prog. Exp. Tumor Res.

    (1970)
  • M.D. Vesely et al.

    Natural innate and adaptive immunity to cancer

    Annu. Rev. Immunol.

    (2011)
  • R. Kiessling et al.

    Natural killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell

    Eur. J. Immunol.

    (1975)
  • R. Kiessling et al.

    Natural killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype

    Eur. J. Immunol.

    (1975)
  • H.G. Ljunggren et al.

    Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism

    J. Exp. Med.

    (1985)
  • K. Karre et al.

    Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy

    Nature

    (1986)
  • C. Guillerey et al.

    NK cells and cancer immunoediting

    Curr. Top. Microbiol. Immunol.

    (2016)
  • M.J. Smyth et al.

    Differential tumor surveillance by natural killer (NK) and NKT cells

    J. Exp. Med.

    (2000)
  • L. Ruggeri et al.

    Allogeneic hematopoietic transplantation and natural killer cell recognition of missing self

    Immunol. Rev.

    (2006)
  • L. Ruggeri et al.

    Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants

    Science

    (2002)
  • Y.T. Bryceson et al.

    Activation, coactivation, and costimulation of resting human natural killer cells

    Immunol. Rev.

    (2006)
  • L.L. Lanier

    NK cell recognition

    Annu. Rev. Immunol.

    (2005)
  • F.M. Karlhofer et al.

    MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells

    Nature

    (1992)
  • A. Moretta et al.

    P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities

    J. Exp. Med.

    (1993)
  • A. Pessino et al.

    Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity

    J. Exp. Med.

    (1998)
  • M. Vitale et al.

    NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis

    J. Exp. Med.

    (1998)
  • Cited by (208)

    • Recent advances of ultrasound-responsive nanosystems in tumor immunotherapy

      2024, European Journal of Pharmaceutics and Biopharmaceutics
    • Immunologic aspects of preeclampsia

      2024, AJOG Global Reports
    View all citing articles on Scopus
    View full text