Natural killer cell immunotherapies against cancer: checkpoint inhibitors and more

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Review

Natural killer cell immunotherapies against cancer: checkpoint inhibitors and more ⁎

Laura Chiossonea, , Margaux Viennea, Yann M. Kerdilesa, Eric Viviera,b a b

Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France Service d’Immunologie, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France

A R T I C L E I N F O

A B S T R A C T

Keywords: NK cells Innate lymphoid cells (ILC) Cancer Immune checkpoint inhibitors (ICI) Immunoreceptor tyrosyne-based inhibitory motif (ITIM)

After many years of research, recent advances have shed new light on the role of the immune system in advanced-stage cancer. Various types of immune cells may be useful for therapeutic purposes, along with chemical molecules and engineered monoclonal antibodies. The immune effectors suitable for manipulation for adoptive transfer or drug targeting in vivo include natural killer (NK) cells. These cells are of particular interest because they are tightly regulated by an array of inhibitory and activating receptors, enabling them to kill tumor cells while sparing normal cells. New therapeutic antibodies blocking the interactions of inhibitory receptors (immune checkpoint inhibitors, ICI) with their ligands have been developed and can potentiate NK cell functions in vivo.

1. Introduction NK cells are a population of innate lymphoid cells (ILCs) that can induce the death of allogeneic and autologous cells undergoing malignant transformation or microbial infection [1]. They account for 5–15% of total peripheral blood mononuclear cells (PBMCs) in humans and they contribute to tumor immunosurveillance through their ability to circulate between peripheral organs. NK cells were shown, years ago, to be important in the anti-tumor response in mice [2,3]. In humans, cases of selective NK cell deficiency are rare and it is difficult to assess the contribution of these cells to the incidence of cancer. However, several studies have revealed the existence of a link between low levels of NK cell activity in peripheral blood and an increase in the risk of cancer [4,5]. In addition, the infiltration of NK cells into tumors has been shown to be associated with a favorable prognosis in non-small cell lung cancer (NSCLC), clear cell renal cell cancer and colorectal cancer [6–8]. NK cells express a repertoire of activating and inhibitory receptors enabling them to detect target cells while sparing normal cells (Fig. 1). The activation status of NK cells is determined by the integration of all these signals [9]. NK cells can detect an absence of major

histocompatibility complex (MHC) class I (“missing self”) [2] through the expression of KIRs (killer cell immunoglobulin-like receptors) in humans [10] and Ly49 receptors in mice [11]. The KIR gene family has been characterized in detail and shown to include a number of different genes and alleles giving rise to distinct haplotypes. Each receptor recognizes a group of classical HLA class I allotypes with particular features of the α1 domain in common [12]. Inhibitory KIRs signal through the immunoreceptor tyrosine-based inhibitory motif (ITIM) in their cytoplasmic domain [13]. The binding of inhibitory KIRs to their ligands leads to the tyrosine phosphorylation of their ITIMs and activation of the SHP-1 protein tyrosine phosphatase, resulting in an inhibition of NK cell activation. The engagement of NK cell receptors by MHC-I molecules during NK cell maturation is required, for the generation of functional effector cells adapted to the host-specific MHC-I environment; this process is referred to as NK cell education [14]. A related family of receptors recognizing MHC class I molecules, the Iglike transcripts (ILT) or leukocyte Ig-like receptors (LIR), can be detected on subsets of NK cells. In particular, ILT2 (LIR-1) and ILT4 (LIR2) contain cytoplasmic ITIMs that recruit SHP-1 and help to control NK cell activation [15]. NK cells also have another inhibitory receptor,

Abbreviations: NK, natural killer; ICI, immune checkpoint inhibitors; ILCs, innate lymphoid cells; PBMCs, peripheral blood mononuclear cells; NSCLC, non-small cell lung cancer; MHC, major histocompatibility complex; KIRs, killer cell immunoglobulin-like receptors; ITIM, immunoreceptor tyrosine-based inhibitory motif; ILT, Ig-like transcripts; LIR, leucocyte Ig-like receptors; MHC, major histocompatibility complex; HLA, human leukocyte antigen; ADCC, antibody-dependent cell-mediated cytotoxicity; TNF, tumor necrosis factor; TRAIL, tumornecrosis factor-related apoptosis-inducing ligand; IFN, interferon; MCP-1, monocyte chemoattractant protein 1; MIP, macrophage inflammatory protein; RANTES, regulated on activation, normal T cell expressed and secreted; IL, interleukin; GM-CSF, granulocyte-macrophage colony-stimulating factor; mAb, monoclonal antibody; GVHD, graft versus host disease; CAR, chimeric antigen receptor; TGF, transforming growth factor; CLL, chronic lymphocytic leukemia; SHP, Src homology region 2 domain-containing phosphatase; SHIP, phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase; AML, acute myeloid leukemia ⁎ Corresponding author. E-mail address: [email protected] (L. Chiossone). http://dx.doi.org/10.1016/j.smim.2017.08.003 Received 9 June 2017; Accepted 3 August 2017 1044-5323/ © 2017 Elsevier Ltd. All rights reserved.

Please cite this article as: Chiossone, L., Seminars in Immunology (2017), http://dx.doi.org/10.1016/j.smim.2017.08.003

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Fig. 1. Human NK cell receptors. Major activating (green) and inhibitory (red) receptors expressed by human NK cells are reperesented [9,91–94]. Abbreviations: AICL, activation-induced C-type lectin; BAT3, HLA-Bassociated transcript 3; HA, hemagglutinins; HIV, human immunodeficiency virus; HN, hemagglutinin neuraminidases; HVEM, herpesvirus entry mediator; LIGHT, homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes; NKp44L, NKp44 ligand; PCNA, proliferating cell nuclear antigen; Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1).

degranulation, a process involving the exocytosis of lytic granules containing perforin and granzymes. In addition to this degranulationdependent pathway, another pathway involving interactions between the TNF family of death receptors and their ligands (such as TRAIL and FasL) may lead to target cell apoptosis [20]. NK cells also secrete proinflammatory cytokines, such as IFN-γ and TNFα, which have direct antitumor effects, many chemokines, including MCP-1, MIP1-α, MIP1β, RANTES, lymphotactin and IL-8 (in decidua), and growth factors, such as GM-CSF, which help to determine the orientation of the adaptive immune response [21]. We discuss here the potential use of NK cells to treat solid and hematopoietic tumors, focusing particularly on the use of infusions of monoclonal antibodies (mAbs) blocking the interactions of inhibitory NK cell receptors with their ligands to enhance NK cell functions in vivo.

CD94/NKG2A, which is expressed as a heterodimer in humans and mice. This receptor recognizes the non-classical MHC class I molecules corresponding to HLA-E in humans and Qa-1b in mice. Unlike classical HLA-A, −B, and −C molecules, which bind and present self-peptides, HLA-E binds leader peptides derived from the signal sequences of certain HLA-A, −B, −C and −G molecules. The interaction between CD94/NKG2A complexes and HLA-E molecules therefore allows NK cells to monitor the expression of other MHC-I molecules indirectly [16]. During tumor transformation, cells often present a decrease in MHCI molecule expression, which identifies them as potential targets for NK cells [17]. However, the destruction of these cells by NK cells also requires the recognition, by activating receptors on the NK cells, of their ligands on the tumor cell membrane. These activating receptors include NKp46, NKG2D, and DNAM-1, in both humans and mice, and NKp30 and NKp44, which are expressed only by human NK cells [18]. NKp30 and NKG2D detect molecules that are not present in the basal state, but for which expression increases in response to stress or pathogen infection. Other surface trigger molecules, such as 2B4, NKp80, NTB-A, and CD59 appear to function as coreceptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor [18]. Most mature NK cells also express CD16 (FcγRIIIA), a low-affinity receptor for the Fc region of G-type immunoglobulins (IgG) responsible for antibody-dependent cell-mediated cytotoxicity (ADCC) [19]. Recognition of the target leads to NK cell activation and

2. NK cell manipulations in therapeutic approaches The discovery that NK cells can recognize and lyse tumor cells translated into hope that NK cells could be used as therapeutic tools. Many efforts have been made to exploit NK cells in clinical practice, and more than 200 (see on clinicaltrials.gov) clinical trials have been carried out with the aim of potentiating the effector capacities of these cells in vivo [17,22,23].

2

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Fig. 2. NK cell-based therapies. A. NK cells are purified from the peripheral blood of a healthy donor and activated in vitro with cytokines (IL-2 or IL-15) before being injected into the patient. The best responses are obtained when the donor does not express KIRs that recognize the patient's HLA molecules, so that infused NK cells do not receive inhibitory signals from cancer cells. B. NK cells are purified from the peripheral blood of the patient and genetically modified to express a chimeric receptor specific for a tumor antigen (CAR) or other molecules able to direct NK cells more efficiently against their targets. Then, modified CAR-NK cells are infused into patient where, after encounter with tumor cells, they undergo activation and expansion. C. Immune stimulatory cytokines are administered to patients to induce the activation and expansion of the autologous NK cell population. The cytokine inducing the strongest antitumor response is IL-2, but this molecule also has major adverse effects, such as expansion of the regulatory T-cell (Treg) population and tissue inflammation, limiting its use.

increasing the specificity of NK cells for tumors through the use of chimeric antigen receptors (CARs) (Fig. 2B). Various preclinical studies are underway to explore the use of CAR-NK cells expressing a receptor specific for CD19 or CD20 in B-cell diseases [27,28]. In an alternative approach, NK cells transduced with retroviruses to express NKG2D or TRAIL have been found to display enhanced tumor recognition and killing in preclinical studies [29,30]. Another strategy is to protect NK cells from the immunosuppressive effect of the TGF-β present in the tumor microenvironment, using a dominant negative receptor II for TGF-β [31], or to improve the survival of NK cells in vivo through the forced expression of IL-2 or IL-15 [32–34].

2.1. Infusion of purified activated NK cells This strategy involves the purification of NK cells from a healthy donor, their culture with cytokines stimulating the immune response (IL-2 or IL-15) and their injection into patients (Fig. 2A). This approach has proved effective and safe [24], but is limited by the poor capacity of the infused NK cells to persist and proliferate in the patient. Given recent findings concerning ILC complexity, it might be possible, in the future, to design new therapeutic strategies targeting different ILC populations. For example, in patients undergoing hematopoietic stem cell transplantation to treat hematologic malignancies, there is evidence to suggest that ILCs expressing activating NK cell receptors (i.e. NCR+ILC3) may protect against acute graft-versus-host disease (GVHD), probably by enhancing tissue repair [25,26]. These data require confirmation, but they could open up new possibilities for treatment by ILC infusion or, more likely, the administration of ILC-derived molecules (such as IL-22) involved in mucosal healing.

2.3. Cytokine infusions Clinical studies are currently underway to evaluate the efficacy and side effects of cytokines, such as IL-2, IL-15 and IL-12, in several types of cancer (Fig. 2C). Rosenberg et al. reported a response rate of 20% for the combination of lymphokine-activated killer cells (LAK cells) and IL2 in patients with melanoma or metastatic renal cell carcinoma [35]. However, the major problem with this approach is that toxicity depends on a broad exacerbation of immune system activation, resulting in neuropathy, capillary leak syndrome, and renal failure. IL-15 is an attractive alternative to IL-2 that has already been investigated in patients with metastatic melanoma and metastatic renal cell cancer [36].

2.2. Gene modification in NK cells to improve the efficacy of adoptive immunotherapy New gene therapy methods designed to enhance NK cell function against tumor cells have been developed and are currently being tested in preclinical and clinical trials. One promising approach involves 3

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Fig. 3. Infusion of receptor-specific mAbs. A. Monoclonal antibodies directed against tumor antigens can also bind to the FcγRIIIA receptor expressed by NK cells and induce NK-mediated ADCC. B. The infusion of mAbs directed against inhibitory NK cell receptors blocks the interactions of these receptors with their ligands, enabling NK cells to kill their target cells efficiently. Some inhibitory receptors (such as KIRs and NKG2A) are also expressed by cytotoxic T lymphocytes, and mAb administration can also restore T cell functions.

3. Immune checkpoint inhibitors in clinical or preclinical development

2.4. Infusion of tumor antigen-specific antibodies to induce NK cell ADCC A number of clinically approved therapeutic antibodies targeting tumor-associated antigens (such as rituximab, anti-CD20 mAb, or cetuximab, anti-EGFR mab) function at least partially by initiating NKmediated ADCC [37,38], (Fig. 3A). Several approaches to increasing the affinity of the activating receptor FcγRIIIA for the Fc region of IgG have been tested, including mutation and glycosylation. Such approaches recently resulted in the approval of mogamulizumab, a low-fucose antiCCR4 mAb for the treatment of T-cell lymphomas [39], and obinutuzumab, an anti-CD20 mAb for the treatment of chronic lymphocytic leukemia (CLL) [40].

Immune checkpoint inhibitors (ICI), such as blocking antibodies, constitute a real revolution in cancer therapy. They have been shown to be effective and to have manageable safety profiles for the treatment of several types of cancer. Their use has resulted in long-term survival in some patients with cancers for which significant therapeutic advances have been made, such as metastatic melanoma and NSCLC. The identification of inhibitory pathways of immune responses has thus constituted a seminal series of discoveries greatly increasing our understanding of and ability to manipulate immunity. Most inhibitory receptors have at least one ITIM in their cytoplasmic domain. These motifs are phosphorylated and recruit tyrosine phosphatase proteins (SHP-1/2 or SHIP). Bioinformatics analyses of entire genes of human genome revealed the presence of more than 300 type I and type II integral membrane proteins with at least one ITIM domain [43]. Only a few of these receptors are currently targeted in therapeutic approaches (Table 1) and they are treated in the next paragraphs.

2.5. Infusion of antibodies directed against inhibitory NK cell receptors (immune checkpoint inhibitors) The aim of this approach is to increase the reactivity of endogenous NK cells by treating patients with mAbs that block the engagement of inhibitory NK receptors (Fig. 3B). With some mAbs, such as rituximab, the ADCC mediated by NK cells is under the control of inhibitory receptors [10,41]. The use of antibodies blocking the interaction of certain inhibitory receptors with their ligands makes it possible to potentiate the antitumor NK cell response in vivo. No molecule truly specific to NK cells has been identified, but some surface receptors are expressed principally by NK cells and play a major role in regulating their function [42]. These molecules activate negative signaling pathways and function as immune checkpoints in the control of cytotoxicity. It took several decades of recent to appreciate the role of the immune system in cancer patients, because tumors effectively suppress immune responses by activating pathways that normally regulate immune homeostasis.

3.1. KIRs The inhibitory receptors KIR2DL1, KIR2DL2 and KIR2DL3 bind to HLA-C on target cells and are involved in the control of NK cell cytotoxicity and cytokine production [44]. The role of KIR receptors in the NK cell antitumor response has been formally demonstrated in patients with acute myeloid leukemia (AML) undergoing haploidentical bone marrow transplantation [45]. Indeed, the subgroup of adult patients receiving KIR/HLA-C-mismatched bone marrow transplants had significantly lower rates of relapse without GVHD, resulting in significantly better survival in follow-up studies [46]. This finding suggests that donor-derived alloreactive NK cells can mediate safe and durable antitumor immunity. A therapeutic mAb blocking the three inhibitory KIR receptors for HLA-C was generated to mimic this 4

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Table 1 NK cell receptor/ligand-targeting drugs in clinical or preclinical development. Lymphocyte receptor

Tumor ligand

Drug

Status

KIR2DL1/2/3 NKG2A PD-1

HLA-C HLA-E PD-L1/-L2

PD-L1

PD-1

LAG3

HLA-II

Tim-3

Gal-9, CEACAM1, Phosphatidylserine, LILRB2

TIGIT

CD155, CD112

VISTA

unknown

unknown

B7-H3

IPH/BMS: lirilumab IPH: monalizumab BMS/ONO: nivolumab, Merck: pembrolizumab Regeneron/Sanofi: REGN2810 Novartis: PDR001 AZN: MEDI0680 Janssen: JNJ-63723283 Pfizer: PF-06801591 Agenus/Incyte: INCSHR1210 Roche: atezolizumab, AZN: durvalumab Pfizer/Merck KGa: avelumab Eli Lilly: LY3300054 BMS: BMS-986016 Prima BioMed: IMP321 Novartis: LAG525 Regeneron/Sanofi: REGN3767 GSK: GSK2831781 Anaptys/Tesaro Merck Macrogenics (PD-1 bispecific) Novartis: MBG453 Anaptys/Tesaro: TSR-022 Eli Lilly: LY3321367 Jounce/Celgene Roche OMP: OMP-313M32 Roche Merck BMS Janssen: JNJ-61610588 Igenica: IGN381 MacroGenics: enoblituzumab

phase II phase II marketed (Opdivo) marketed (Keytruda) phase II phase II phase I/II phase I/II phase I phase I marketed (Tecentriq) approved (Imfinzi) approved (Bavencio) phase I phase II phase I/II phase I phase I phase I preclinical preclinical preclinical phase I phase I phase I preclinical preclinical phase I phase I preclinical preclinical phase I preclinical phase I

of anti-PD-1 blocking mAbs and their ability to induce immune systemstimulating cytokines such as IFN-γ, which may boost NK cells, the use of lirilumab in combination with nivolumab is also being explored as a means of achieving the functional restoration of both NK and T cells, in solid tumors (NCT01714739) and hematological malignancies (NCT01592370). In two phase I clinical trials in patients with advanced solid tumors, this combination was found to be no more toxic than nivolumab monotherapy (Segal N.H. et al., unpublished). More recently, a phase I/II trial showed combination treatment with lirilumab and nivolumab to be effective in patients with advanced chemoresistant head and neck carcinoma (Leidner R. et al., unpublished). This study was a single-arm study, with no control population, but well-established historical control data for head and neck cancers are available for outcome assessment. It showed that lirilumab was well-tolerated in the population of patients with head and neck cancers. Follow-up is still underway and the data are still being processed. The efficacy results are encouraging but must be interpreted in the context of a fairly small single-arm study. Overall survival was 90% at 6 months and 60% at 12 months, for patients treated with the lirilumab and nivolumab combination treatment, but only 55.6% and 36%, respectively, for nivolumab alone, which recently obtained FDA approval for this indication. These preliminary clinical data suggest a very interesting tail of the curve for head and neck cancers patients, similar to that reported for other cancers, such as melanoma treated with a PD-1 or CTLA-4 immune checkpoint inhibitors. A detailed evaluation of immunocorrelative biomarkers would also be very useful. The results of a randomized, double-blind, placebo-controlled phase II clinical trial (EffiKIR) evaluating the efficacy of lirilumab monotherapy in elderly patients with AML have recently been released (NCT01687387). This study did not meet the primary efficacy endpoint, but it confirmed the safety profile of lirilumab monotherapy. The two treatment arms of the trial tested lirilumab as a single agent, at different

strategy: 1–7F9 is a fully human IgG4 that increases NK cell cytotoxicity in HLA-C-expressing tumor cells. This effect was demonstrated in vitro, with patient-derived AML blasts targeted by autologous or heterologous NK cells, and was confirmed in a humanized AML mouse model [47]. The efficacy of this approach was also demonstrated in a syngeneic tumor model in which Ly49C/I blockade with a specific mAb induced the selective rejection of tumor cells by NK cells, with the sparing of normal tissues [48]. These findings led to clinical development of a hybridoma-derived product, IPH2101, which was tested in several phase I clinical trials [49–52]. These trials showed KIR blockade to be safe, with minimal side effects, and worthy of further clinical investigation. Lirilumab (IPH2102, BMS-986015), a stabilized recombinant IgG4 of identical antigen specificity, was then developed to increase the stability and manufacturability of the mAb. This antibody is currently being tested in several phase I and II trials, for maintenance monotherapy in elderly AML patients (NCT01687387), and in combination with the tumor-targeting mAb elotuzumab (anti-SLAMF7/ CD319) in multiple myeloma (NCT02252263), the DNA hypomethylating agent 5-azacytidine in AML (NCT02399917) and myelodysplastic syndromes (NCT02599649), or rituximab in CLL (NCT02481297). Interestingly, studies in vitro and in vivo have shown that lirilumab enhances rituximab-induced ADCC [53]. A phase II clinical study assessing the efficacy of lirilumab monotherapy in patients with multiple myeloma was recently stopped early due to a lack of efficacy [54]. According to the authors, this lack of efficacy may be due to a selective decrease in NK responsiveness in KIR2D+ cells, accompanied by a loss of KIR2D expression on the cell surface. However, no such effect has been detected in other clinical trials and these findings therefore require confirmation. It is possible that an adapted therapeutic regimen (intermittent blocking) or combined therapy may be required to induce an effective antitumor response in at least some cancers. For example, given the clinical success 5

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blocking PD-1/PD-L1 interactions have been developed (Table 1) and these antibodies are now being used to treat advanced solid tumors. One of these antibodies, nivolumab, has been shown to induce the expression in T lymphocytes of genes encoding proteins typically involved in cytotoxicity and NK cell function, such as IFNγ and granzyme B [66]. These data suggest that blockade of this checkpoint can rescue the antitumor immune response by acting on the same molecular pathway in both T and NK cells. PD-1 blockade has long been known to re-establish antitumor responses in mice [67,68], but clinical trials have provided important results for cancer patients. Clinical responses to monotherapy have been observed in a wide range of solid and hematologic cancers [69,70]. These responses are often durable and no serious toxicity is observed in most people. Nevertheless, only a minority of people treated with antibodies specific for PD-1 or PD-L1 display a strong response, with rapid reductions of tumor volume by 10–40%, depending on the patient [70]. Various tumor biopsy specimens collected from patients before treatment were examined from a subjected to histological examination, to try to explain this variability, and the relationship between their composition and the grade of response observed in patients was investigated. Three immune profiles correlated with the efficacy of anti-PD-L1/PD-1 therapy were identified [69]. The first, the “inflamed” phenotype, is characterized by the presence in the tumor parenchyma of numerous immune cells located close to the tumor cells. In samples with this profile, the infiltrating immune cells may display staining for PD-L1. This profile is consistent with the presence of a pre-existing antitumor immune response inhibited by immunosuppression in the tumor. Indeed, clinical responses to anti-PDL1/PD-1 therapy are most frequently observed in patients with inflamed tumors. The second profile is the “immune-excluded” phenotype, which is also characterized by the presence of immune cells. However, in this profile, these cells are retained within the stroma surrounding the tumor cells and they do not penetrate the parenchyma. The third profile, the “immune-desert” phenotype, is characterized by a lack of hematopoietic cells in either the parenchyma or the stroma of the tumor. This phenotype probably reflects an absence of pre-existing antitumor immunity and, unsurprisingly, these tumors rarely respond to anti-PD-L1/PD-1 therapy [71]. By contrast, not all tumors characterized by an immune-inflamed profile respond to anti-PD-L1/PD-1 treatment. In cases in which there is no response to treatment, other immune checkpoints are probably responsible for inhibiting the antitumor response [72].

doses and treatment intervals (0.1 mg/kg every 3 months or 1 mg/kg every 4 weeks) and the patients in the third arm received placebo. There was no statistically significant difference between either of the lirilumab arms and the placebo arm in terms of leukemia-free survival (LFS) or any of the other efficacy endpoints. The 1 mg/kg arm of the trial was discontinued as the objective of achieving a superior LFS in this arm relative to placebo was not attained. No tolerance problems were reported. The data analysis is still underway and should provide a clearer interpretation of the results of this trial. Lirilumab is still being assessed in six trials, for a range of solid and hematological cancer indications, in combination with other agents, including nivolumab (see clinicaltrials.gov). 3.2. NKG2A NKG2A is an inhibitory receptor expressed by most NK cells and some cytotoxic T lymphocytes. It recognizes HLA-E molecules in humans and Qa-1 in mice. The expression of HLA-E, unlike that of classical HLA class I molecules, is conserved, and may even increase, in 50–80% of patients with solid tumors or leukemia/lymphoma [6,51,55,56]. A study on NSCLC showed that the NK cells infiltrating the tumor had low levels of expression for activating receptors and KIRs, whereas NKG2A expression was unaffected by tumor microenvironment [6]. HLA-E was strongly expressed on tumor cells but was not expressed on the surrounding epithelial cells. The expression of NKG2A on tumor-infiltrating NK and T cells has also been confirmed in breast and cervical cancer, and appears to be related to the secretion of IL-15 and TGF-β by tumor cells [55,57]. A study in melanoma patients demonstrated that the effector functions of tumor antigen-specific CD8+ T cells expressing NKG2A were inhibited by this receptor [58]. Accordingly, tumor infiltrating CD8+ T cells were identified associated with a favorable prognosis of NSCLC only in patients with tumors expressing classical HLA class I molecules but not HLA-E [56]. Moreover, increases in HLA-E expression (documented in 20% of patients with colorectal carcinoma) have been shown to be associated with a poor clinical outcome in the presence of massive CD8+ T cell infiltration [59]. All of these results suggest that it is important to block the NKG2A checkpoint to enhance the antitumor immune response, by direct effects on the infiltrating lymphocytes. In a preclinical trial, a humanized mAb specific for NKG2A (Z270) was shown to be effective for increasing the cytotoxicity of NK cells to leukemia and lymphoma cells, both in vitro and in vivo [60]. This antibody was then developed for clinical use under the name monalizumab. It is currently being tested in phase II clinical trials as a single agent for the treatment of gynecologic malignancies (NCT02459301) and for the preoperative treatment of squamous cell carcinoma of the oral cavity (NCT02331875), and in combinations with cetuximab (an anti-EGFR mAb) for head and neck cancer (NCT02643550), with ibrutinib (a BTK inhibitor) for CLL (NCT02557516), and with durvalumab (an anti-PD-L1 mAb) for various solid tumors (NCT02671435).

3.4. LAG3 Lymphocyte-activation gene 3, also known as LAG3, is a cell surface molecule from the immunoglobulin superfamily that is expressed by activated T lymphocytes, NK cells, B cells, and plasmacytoid dendritic cells. This molecule with diverse biological effects acts as a ligand for MHC class II molecules, to which it binds with a very high affinity. This immune checkpoint receptor downregulates the proliferation, activation, and homeostasis of T cells, and has been reported to play a role in the suppressive function of Tregs [73]. Shortly after the discovery of this molecule, experiments in LAG3-deficient mice suggested that LAG3 was crucial for NK cell function [74]. Killing of certain tumor targets by NK cells from these mice was inhibited, whereas lysis of cells displaying MHC class I disparities remained intact. This suggests the existence of a LAG-3 dependent and a LAG-3 independent NK cell cytotoxicity, that may be operational in the same cell. However, LAG3 was also found to be expressed on tumor-infiltrating CD8+ T cells and to inhibit the proliferation and IFNγ production of these cells [75]. Later studies therefore focused principally on the role of LAG3 in regulating adaptive immunity. LAG3 is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. The predicted mechanism of action of LAG3-specific mAbs involves the relief of negative regulation of NK and T cells. MHC class II molecules are generally expressed only by

3.3. PD-1 PD-1 is an inhibitory receptor that binds PD-L1 and PD-L2, its specific ligands, expressed on several types of tumor and infected cells, but also by professional antigen-presenting cells (APCs) present in inflammatory foci. This receptor was initially described on T, B and myeloid cells [61], but more recent studies have described the expression of PD-1 on NK cells from healthy individuals [62,63]. In addition, NK cells expressing PD-1 were also detected in cancer patients, including Kaposi sarcoma or ovarian carcinoma [64,65]. Studies in vitro demonstrated that engagement of the PD-L1 expressed on tumor cells inhibited their lysis by NK cells, whereas the blockade of PD-1 with mAbs restored NK cell function and favored the migration of NK cells towards the tumor site. In the last few years, several antibodies 6

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tumor models [88]. TIGIT is strongly expressed on tumor-infiltrating lymphocytes in a broad range of tumors. In CD8+ T cells from melanoma patients, the blockade of both TIGIT and PD-1 resulted in additive improvements in cell proliferation, cytokine production, and degranulation [89]. This combined treatment resulted in complete tumor rejection in preclinical models [90]. TIGIT acts in synergy not only with PD-1, but also with Tim-3, to impair protective antitumor responses [88]. The joint blockade of either TIGIT and PD-1 or TIGIT and Tim-3 therefore promotes antitumor immunity and induces tumor regression. A fully human anti-TIGIT mAb (MTIG7192A, RG6058) is currently being tested in a phase I clinical trial in combination with anti-PD-1 therapy, in various solid tumors.

APCs, but some cancer cells have also been reported to express these molecules. LAG3 interaction with the MHC class II molecules expressed by melanoma cells has been shown to protect these cells against FASmediated apoptosis [76]. LAG3 also encodes an alternative splice variant that is translated to yield a soluble form of LAG3 (sLAG3) that acts as an immune adjuvant [77]. Although sLAG3 is not the intended target in clinical trials of LAG3-specific mAbs, the role of this molecule should not be ignored. Interestingly, sLAG3 is thought to bind only to MHC class II molecules present in lipid raft microdomains on a minor subset of APCs. A clinical-grade soluble form of LAG3 protein (LAG3-Ig fusion protein, IMP321), a physiological high-affinity MHC class II binder, has been shown to induce IFN-γ and TNFα production by NK cells and CD8+ T cells in short-term ex vivo assays [78]. IMP321 is currently used to stimulate the immune system in phase I and phase II clinical trials, as an adjunct to standard chemotherapy and in combination with anti-PD1 therapy, respectively. BMS-986016, an anti-LAG3 mAb, is currently being tested in phase II clinical trials. A number of additional LAG3 antibodies are currently in preclinical development. LAG3 may be a useful checkpoint inhibitor that can both activate T and NK effector cells and inhibiting the suppressive activity of Tregs [79]. Therapy combining LAG3 targeting with nivolumab (NCT01968109) treatment is currently being evaluated in subjects with selected advanced (metastatic and/or non-resectable) solid tumors.

4. Conclusion Recent breakthroughs in treatment reflect decades of research focusing on improving our understanding of the biological basis of cancer and unlocking the power of the immune system. The therapeutic targeting of immune checkpoints has yielded outstanding results in patients with various types of cancer. However, despite the clinical success of mAbs against PD-L1/PD-1 and the expectations accompanying the clinical development of antibodies blocking other immune checkpoints (Table 1), long-lasting responses have been achieved in only a subset of patients. The immune profile of an individual reflects the contributions of an array of factors, including the intrinsic properties of the tumor and environmental factors, such as infectious agents. This suggests that a broader view of cancer immunity is required. Further studies are required to identify all the receptors involved in the regulation of NK cell cytotoxicity, for the development of mAbs blocking the interactions of these receptors with their ligands, thereby enhancing the antitumor NK cell response. Histologic examinations of tumor biopsy specimens should make it possible to identify the patients most likely to respond to treatments blocking the various receptors, guiding targeted tumor- and patient-specific therapy. An important issue related to the employment of checkpoint inhibitors is their toxic side effects, that arise quite frequently and necessitate proper treatments, as they can be severe in the case of colitis, dermatitis, hypophysitis and fatigue. An important feature of Lirilumab is the lack of toxicity associated with its use in acute myeloid leukemia in monotherapy [52], and in solid tumors in combination therapy with Nivolumab (Segal N.H. et al., unpublished). Interestingly, an absence of toxicity was also observed in various clinical trials of NK cell adoptive cell therapy. It remains to be explored whether this lack of toxicity of activated NK cells could be also reproduced using checkpoint inhibitors targeting NK cell receptors other than Lirilumab. If it was the case, this would be a great advantage of NK cell-based therapies.

3.5. Tim-3 Tim-3 is a type I glycoprotein expressed by innate and adaptive immune cells. It was first identified as a molecule selectively expressed on IFN-γ–producing CD4+ T helper 1 (Th1) and CD8+ cytotoxic T cells. Tim-3 is also constitutively expressed by functional and mature NK cells. Upon activation, it functions as an inhibitory receptor on NK and T cells, reducing cytotoxicity and cytokine production [80,81]. Tim-3 is also found on T cells in patients with advanced melanoma, NSCLC, and follicular B-cell non-Hodgkin lymphoma. In these three cancers, all Tim-3+ T cells coexpress PD-1 and display impaired proliferation and cytokine production [82]. A recent study reported an increase in Tim-3 expression on circulating NK cells in advanced melanoma patients and a correlation between this increase and the exhausted phenotype of these cells [83]. In patients with lung adenocarcinoma, a blockade of Tim-3 signaling with mAbs increases the cytotoxicity and IFN-γ production of peripheral NK cells [84]. Thus, Tim-3 expression in NK cells can be used as a prognostic biomarker in human cancers. Anti-Tim-3 blocking mAbs are currently being tested in phase I clinical trials and preliminary data have suggested that they could be used in combination with anti-PD-1 therapy. Indeed, in the setting of anti-PD-1 therapy, treatment failure is associated with an upregulation of alternative immune checkpoints (including Tim-3), whereas resistance to anti-PD-1 therapy was prevented by the administration of an anti-Tim-3 mAb with an anti-PD-1 agent [72].

5. Competing interests E.V. is a co-founder of and shareholder in Innate-Pharma. The other authors declare no competing interests.

3.6. TIGIT

Acknowledgments

TIGIT (T cell immunoglobulin and ITIM domain) is a receptor of the Ig superfamily that is expressed on NK cells and on effector, memory, and regulatory T cells, where it functions as a co-inhibitory receptor [85–87]. It binds two ligands, CD155 (PVR) and CD112 (PVRL2, nectin2), expressed on APCs, T cells, and various types of non-hematopoietic cell, including tumor cells. CD226 (DNAM-1) binds to the same ligands, but with lower affinity. TIGIT can inhibit the interaction between CD226 and CD155. TIGIT engagement induces the phosphorylation of this receptor and the recruitment of SHIP1 (SH2 domain-containing inositol-5-phosphatase 1), leading to an inhibition of NK cell cytotoxicity, granule polarization, and cytokine secretion [86,87]. Upon interaction with CD155 and CD112, which are strongly expressed on tumor cells, TIGIT downregulates antitumor responses. Indeed, TIGIT-deficient mice display a significant delay of tumor growth in two different

E.V. lab is supported by a European Research Council advanced grant, Agence Nationale de la Recherche, Ligue Nationale contre le Cancer (Equipe labellisée “La Ligue,”), institutional grants from INSERM, CNRS, Aix-Marseille University and Marseille Immunopole to the CIML References [1] H. Spits, D. Artis, M. Colonna, A. Diefenbach, J.P. Di Santo, G. Eberl, S. Koyasu, R.M. Locksley, A.N. McKenzie, R.E. Mebius, F. Powrie, E. Vivier, Innate lymphoid cells–a proposal for uniform nomenclature, Nat. Rev. Immunol. 13 (2) (2013) 145–149.

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