Receptors that interact with nectin and nectin-like proteins in the immunosurveillance and immunotherapy of cancer

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Management of an immune response is achieved through a delicate balance of pro-inflammatory and anti-inflammatory mechanisms. Controlling this response requires co-operation between a multitude of immune cells that are in turn controlled by specific receptor-ligand interactions and cytokine networks. In the context of cancer, a major mechanism by which the immune system restrains disease is through the action of cytotoxic lymphocytes that include natural killer (NK) cells and CD8 T cells. Both of these cell types express a panoply of receptors that are able to control their responses in order to heighten the specificity of their effector function. An emerging class of such receptors on cytotoxic lymphocytes are a group of immunoglobulin superfamily members that interact with ligands of the nectin and nectin-like (necl) family. These receptors include CD226, TIGIT, CRTAM and CD96. This review will outline the immunobiology of these receptors, the contexts where their function is important, their role in tumour immunosurveillance, and how they may be utilised for therapeutic applications in cancer.

Highlights

NK cell and CD8 T cell receptors are important in recognition and control of cancer. ► Immunoglobulin receptors on NK cells and CD8 T cells can recognise nectin and nectin-like (necl) proteins on cancer. ► Immunoglobulin receptors that bind nectin and necl proteins include CD226, TIGIT, CRTAM and CD96. ► This review outlines the function of these receptors in cancer immunosurveillance and immunotherapy of cancer.

Introduction

Both natural killer (NK) cells and CD8 T cells express a range of receptors that are able to regulate their responses to pathogens and cancer. Contact-dependent NK cell function is highly regulated by the relative interactions of non-antigen specific activating, inhibitory and co-stimulatory molecules that bind to their cognate ligands on a target. In contrast, CD8 T cell function is largely dependent on antigen-specific MHC class I: TCR interactions along with fine-tuning from co-stimulatory molecules.

The major inhibitory receptors on NK cells are those that bind MHC class I and MHC class I-related molecules. These include specific subsets of Ly49 receptors in mice and killer immunoglobulin-like receptors in humans, as well as NKG2A in both species. Major activating receptors on NK cells include NKG2D, and the natural cytotoxicity receptor (NCR) NKp46 in mice, and NKp30, NKp44 and NKp46 in humans.

Apart from MHC class I: TCR interactions which can define whether a CD8 T cell becomes activated or anergic (e.g. due to the affinity or length of this interaction), there are a range of co-stimulatory molecules that can finely tune CD8 T cell activity. The major co-stimulatory molecules that have been described on CD8 T cells are those from the CD28 family that interact with members of the B7 family [1]. The CD28 family consists of both positive and negative receptors. Positive receptors act to enhance CD8 T cell activity and such members include CD28 and ICOS. In contrast, negative receptors dampen activity and these include CTLA-4 and PD-1. More interesting and relevant to the observation that a positive receptor CD28, and a negative receptor CTLA-4, can bind to the same ligands being CD80 and CD86.

As the function of the aforementioned receptors has become clear, heightened interest in other receptors that modulate both NK and CD8 T cell function has gained momentum. One group of such receptors that have become intensely studied by many groups are immunoglobulin superfamily receptors that bind to the nectin and nectin-like (necl) family. The major receptors that bind nectin and necl family members are CD226 (DNAM-1, PTA-1, TLiSA1), TIGIT (WUCAM, Vstm3, VSIG9), class I-restricted T cell-associated molecule (CRTAM), and CD96 (T cell-activated increased late expression) (Figure 1). All of these receptors are expressed on both NK cells and CD8 T cells and recent studies have shown that they have important roles in mediating the effector function of both cell types in specific immunological situations. Intriguingly, CD226 and TIGIT may control CD8 T cell effector function through mechanisms analogous to that of CD28/CTLA-4 interactions with CD80/86.

Section snippets

CD226

CD226 was originally described as TLiSA1, a human T cell-lineage specific marker involved in the differentiation of CD8 T cells [2]. It has two immunoglobulin domains and has been reported to interact with 4.1G and discs large, therefore also implicating it in cell adhesion through interaction with the actin cytoskeleton [3]. Most importantly however, is the ability of CD226 to invoke potent cytotoxicity on both T cells and NK cells that has been studied most intensively [4, 5, 6]. The clinical

TIGIT

TIGIT was discovered in 2009 by three groups using genome-wide search strategies as an immune cell-specific immunoglobulin protein of the CD28 family. Upon full characterisation, its structure showed it contained one extracellular immunoglobulin domain, a type 1 transmembrane region and two ITIM motifs [18••, 19, 20•]. When searching for binding partners of TIGIT, a unique protein that was identified was CD155. Subsequent analysis of further nectin and necl proteins has shown that TIGIT can

CRTAM

Originally reported in 2000, CRTAM was identified utilising a cDNA library generated from natural killer T cells [24]. The structure of CRTAM is similar to that of CD226 and contains two extracellular immunoglobulin domains [25]. Thus far it has been characterised to bind to only one ligand, the nectin-like family member 2 (necl-2, TSLC1) [26, 27, 28]. Numerous studies that have analysed expression of CRTAM on lymphocytes have shown that it is only expressed upon their activation, and this is

CD96

CD96 is the least characterised immunoglobulin receptor that binds to nectin and necl proteins and its function has yet to be confirmed. CD96 was originally cloned and identified in human T cells and has three extracellular immunoglobulin domains and an ITIM motif [25, 33]. In humans, its expression is largely confined to NK cells, CD8 T cells and CD4 T cells. The major ligand of CD96 is CD155, but has also been reported to associate with CD111 (nectin-1) [34, 35].

Since two other immunoglobulin

Concluding remarks

The interest in cancer therapeutics surrounding the function of receptors that govern NK and CD8 T cell function is growing exponentially, given the recent clinical success of anti-CTLA-4 therapy in melanoma and promising unpublished clinical trial data concerning anti-PD-1. The major functions of immunoglobulin superfamily receptors that bind to nectin and necl proteins have recently been uncovered, and these studies have shown the in vivo and clinical importance of these receptors in

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

CJC is funded by a Leukaemia Foundation of Australia PhD Scholarship and a Monash University Postgraduate Award, DMA is funded by a NHMRC Project Grant, Career Development Fellowship and Cancer Australia and the Cure Cancer Australia Foundation. MJS is funded by a NHMRC Program Grant and Australia Fellowship. We would also like to thank Marco Colonna and Susan Gilfillan for their valuable intellectual and experimental contributions towards this review.

References (37)

  • R. Castriconi et al.

    Natural killer cell-mediated killing of freshly isolated neuroblastoma cells: critical role of DNAX accessory molecule-1-poliovirus receptor interaction

    Cancer Res

    (2004)
  • D. Cho et al.

    Cytotoxicity of activated natural killer cells against pediatric solid tumors

    Clin Cancer Res

    (2010)
  • S. Morgado et al.

    NK cell recognition and killing of melanoma cells is controlled by multiple activating receptor-ligand interactions

    J Innate Immun

    (2011)
  • B. Sanchez-Correa et al.

    Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and their ligands

    Cancer Immunol Immunother

    (2011)
  • C. Bottino et al.

    Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule

    J Exp Med

    (2003)
  • S. Gilfillan et al.

    DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

    J Exp Med

    (2008)
  • C.J. Chan et al.

    DNAM-1/CD155 interactions promote cytokine and NK cell-mediated suppression of poorly immunogenic melanoma metastases

    J Immunol

    (2010)
  • T. Lakshmikanth et al.

    NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo

    J Clin Invest

    (2009)
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