A novel mechanism of antitumor response involving the expansion of CD3+/CD56+ large granular lymphocytes triggered by a tumor-expressed activating ligand

Abstract

We describe a patient with acute myeloid leukemia (AML) who developed polyclonal large granular lymphocyte (LGL) proliferation. The reciprocal evolution of AML and LGLs suggested that these LGLs had an anti-tumor activity. The patient's LGLs killed autologous leukemia cells in a different way to classical T lymphocyte-mediated cytotoxicity since it did not rely on the recognition of target antigens presented by major histocompatibility complex (MHC) class I molecules by the CD3/TcRαβ complex. This killing was also different from natural killer (NK)-mediated cytotoxicity, which depends on the absence of MHC class I molecule recognition by NK inhibitory receptors. The LGLs were polyclonal, had a CD3+/CD8+/CD56+ phenotype, and did not express the natural killer cell receptors (NKRs) for MHC class I molecules. The LGLs did not express the NK-specific activating natural cytotoxicity receptors but expressed the 2B4 non-MHC restricted triggering receptor, whose ligand CD48 was expressed by leukemic cells and normal bone marrow cells. The 2B4 receptor participated in the ability of LGLs to lyse patient's leukemia. This represents a novel function for 2B4 in man, since this molecule, at variance with the murine system, was considered not to have direct effects on CD8+ T cell-mediated cytotoxicity. This case report allowed us to describe a novel T lymphocyte-mediated anti-tumor mechanism which relied on (1) the abnormal expansion of the rare 2B4-positive CD3+/CD8+/CD56+ T lymphocyte subset, (2) an as yet undescribed cytotoxicity mechanism in man which depended on 2B4 molecule. The relevance of this observation in human cancer immunotherapy has to be further investigated.

Introduction

Attempts to identify cellular effectors for immunotherapy have shown evidence of two major cytolytic populations, natural killer (NK) cells and CD3+/CD8+αβ cytolytic T cells. The killing properties of cytolytic T lymphocytes are restricted by MHC molecules since they usually require the recognition by the CD3/TcR complex of target cell peptides presented by MHC class I molecules. In mice models, the CD3+/CD8+/CD56+ T lymphocyte population has a potent in vivo anti-tumor activity.1,2 In man, it has been recently demonstrated that the cytolytic effector function of human CD3+/CD8+ circulating T cells correlates with CD56 surface expression.3 This CD3+/CD8+/CD56+ population represents a rare phenotype (usually ≈1 to 5% of leukocytes1,3) whose lysis capacity is negatively regulated by functional natural killer inhibitory receptors.4,5,6,7,8,9,10,11,12,13,14,15,16 Very recently, it has also been demonstrated that the expression of the 2B4 molecule on CD3+/CD8+αβ correlates with the acquisition of effector cell properties and, putatively, with anti-tumor properties.17 The 2B4 molecule has a wide cellular distribution (monocytes, NK, T lymphocytes).18 In NK cells, 2B4 only functions as a co-receptor, since killing depends on the simultaneous engagement of the natural cytotoxicity receptors (NCRs).19 The 2B4 requirement for an additional co-activation signal could reflect the necessity to counterbalance the effects of inhibitory NK receptors, which are expressed on NK cells and negatively regulate 2B4-mediated cytotoxicity.20

Here we describe a patient with acute myeloid leukemia (AML) who developed polyclonal 2B4-positive CD3+/TcRαβ/ CD8+/CD56+ large granular lymphocyte (LGL) proliferation and experienced a reciprocal evolution of AML blasts and LGLs. These LGLs killed autologous leukemic cells and haematopoietic cells via engagement of the 2B4 activating receptor by its ligand CD48 expressed at the cell surface.

Case report

A 60-year-old man was admitted to hospital for an AML classified as an M4 subtype according to FAB criteria.21 Clinical evolution and treatment are summarized in Figure 1. The patient had asthenia, dyspnea and gingiveal bleeding. Physical examination failed to detect adenopathy or splenomegaly. Hemoglobin (Hb) was 8 g/dl, white blood cells (WBC) 107 × 109/l (61% neutrophils, 4% lymphocytes, 14% monocytes, 5% metamyelocytes, 9% myelocytes and 7% myeloblasts), and platelets 22 × 109/l. The bone marrow (BM, Figure 2a) was hypercellular with few megakaryocytes, had signs of dismyelopoiesis, with myeloblast infiltrate of 41%, and 8% monocytes. Peroxydase staining was positive in 100% blasts, while butyrate esterase was positive in less than 5% blasts. Cytogenetic analysis (50 metaphases) obtained a normal karyotype. The induction treatment was daunorubicin 60 mg/m2 day 1 to day 3, aracytine 100 mg/m2 day 1 to day 10, but failed to obtain complete remission (CR), which was attained only after a second induction (idarubicin 8 mg/m2 day 1 to day 3, aracytine 100 mg/m2 day 1 to day 10). The patient was further treated by consolidation regimen (daunorubicin 60 mg/m2 day 1 and day 3, aracytine 50 mg/m2 day 1 to day 7) followed by intensified consolidation (aracytine 3000 mg/m2 twice a day from day 1 to day 4, daunorubicin 45 mg/m2 day 5 to day 7). Finally, treatment was completed by autologous peripheral blood granulocyte colony-stimulating factor mobilized stem cell transplantation (conditioned by busulfan 4 mg/kg/day for 4 days, melphalan 140 mg/m2 for 1 day). After the aplasia period, peripheral blood counts and BM aspirate (Figure 2b, c) confirmed the CR and the absence of signs of myelodysplasia (Figure 2d). One month later, the patient developed a proliferation of LGLs in the peripheral blood (55% LGLs, Figure 2e) and BM. Physical examination was normal, and the patient was asymptomatic. Repeated viral serologies, hepatic enzyme controls and viremia excluded evolutive Epstein–Barr virus or cytomegalovirus disease and human immunodeficiency virus, human T lymphotropic virus or viral hepatitis infection. The patient developed bicytopenia (platelets 35 × 106/l, Hb 10 g/dl) but repeated BM aspirates failed to detect blast cells or recurrence of myelodysplasia signs (not shown). Persistent LGL proliferation (28–55% in bone marrow, 23–48% in PB) was detected while PB numeration deteriorated, in particular regarding platelets, that dropped to 6–20 × 106/l, leading to repeated cutaneous and diffuse enteric hemorrhages. This symptomatology and repeated transfusion dependency (both red blood cell and platelets) prompted us to treat the LGL proliferation. A very low-dose modified (no steroids) mini-CHOP chemotherapy regimen (cyclophosphamide 500 mg, adriamycin 25 mg and vincristine 2 mg) was administered, in association with oral low-dose (10 mg/m2 weekly) methotrexate.22 The LGLs rapidly cleared from PB and were not detected by day 10. At day 14, increased cytopenia prompted us to perform a new bone marrow aspirate, which failed to detect LGLs but demonstrated overt leukemia relapse since leukemic myeloid blast represented 40% of nucleated cells (Figure 2f). The patient soon died from uncontrollable leukemia proliferation with symptomatic meningeal involvement.

Figure 1
figure1

Reciprocal evolution of leukemic cells and LGLs. The arrow labeled ‘chemotherapy and autologous BMT’ indicates the four courses of chemotherapy (two inductions, two consolidations) followed by busulfan + melphalan-conditioned autologous transplantation. PB, peripheral blood; BM, bone marrow.

Figure 2
figure2

Bone marrow and peripheral blood features. Panel a shows a BM aspirate at initial diagnosis showing features of AML associated with dysgranulopoiesis. Panels b and c correspond respectively to a medium-power and a low-power image of a BM aspirate corresponding to complete remission (CR). Panel d is a high-power image of a BM aspirate at CR, showing myeloid and erythroid cells which lack any signs of dysmyelopoiesis. Panel e shows LGLs in the PB at time of CR. Finally, panel f corresponds to a BM aspirate showing AML relapse and the absence of LGLs.

Methods

Cell obtainment and separation

BM or PB samples were obtained from the patient or normal blood donors after informed consent. Cell separation was performed on Ficoll–Hypaque gradients and viably frozen in liquid nitrogen until use. Since all lymphocytes present in BM were LGLs expressing the CD2 molecule, positive selection of BM infiltrating lymphocytes was performed using a rosetting technique with sheep red blood cells.23 The purity of the preparation (>95%) was further controlled by detection of the markers identified on LGLs (CD8/CD56) and by morphological examination of Giemsa stain of cytocentrifuge preparations.

The ‘normal BM cells’ we used corresponded to mononuclear cells purified on Ficoll–Hypaque gradient from a BM aspirate of the patient at time of CR, from which lymphocytes were removed by negative selection (incubation with anti-CD3 and anti-CD19 mAbs followed by immunomagnetic depletion with goat anti-mouse-coated Dynabeads (Dynal, Oslo, Norway)).

Monoclonal antibodies

The following mAbs were used: JT3A (IgG2a, anti-CD3), (c218 (IgG1, anti-CD56), ST39 (IgG2a, anti-2B4), BAB281 (IgG1, anti-NKp46), Z270 (IgG1, anti-NKG2A), P25 (IgG1, anti-NKG2A + NKG2C), F278 (IgG1, anti-LIR1), A6-136 (IgM, anti-MHC class I), (AM, Molecular Immunology Laboratory), anti-CD4, anti CD8, anti-CD34, anti-CD13, anti-CD33, anti-TCRα/β WT31, (Immunotech, Marseilles, France) and anti-CD48 (Pharmingen, San Diego, CA, USA).

Flow cytometry analysis

When using mAbs produced by ourselves, we performed indirect staining; briefly, cells were incubated with the appropriate mAb followed by PE- or FITC-conjugated isotype-specific goat anti-mouse secondary reagent (Southern Biotechnology Associated, Birmingham, AL, USA). Directly coupled commercially available Mabs were used in one-step direct staining. Samples were analyzed by one- or two-color cytofluorimetric analysis (FACScan Becton Dickinson, Mountain View, CA, USA) as previously described.24

Cell culture and cytolytic activity

Cell cultures were performed in RPMI 1640 (Bioproducts, Walkersville, MD, USA) with 10% fetal bovine serum (Bioproducts). The cytotoxic assays were performed as previously described24 by means of 4-h 51chromium-release assays. Briefly, a fixed target cell number (2000–5000/wells, depending on 51chromium uptake) was used at different ratios of effector cells. The percentage of lysis was determined for each triplicate experiment as [(experimental 51Cr release − spontaneous 51Cr release)/(maximum 51Cr release − spontaneous 51Cr release)] × 100. We used as control the FcγR-positive target P815 (murine mastocytoma). The concentrations of the various mAbs were 10 μg/ml for the masking experiments and 0.5 μg/ml for the redirected killing experiments. All data correspond to at least two independent experiments with triplicate measures.

Results

Primary LGLs display significant spontaneous cytotoxicity against autologous leukemia and hematopoietic cells (Figure 3)

Figure 3
figure3

Cytolytic activity of patient's LGLs. This figure shows the ability of the patient's LGLs (from PB, white squares, or BM, black circles) at four ratios of effector cells to lyse autologous leukemic cells (panel a) or BM autologous non-leukemic cells obtained during AML complete remission (panel b).

To test the hypothesis that LGLs could have some anti-tumor activity, we performed cytotoxicity experiments, using as effector cells, freshly isolated LGLs (either from PB or BM) that were analyzed against patient's autologous target cells. As shown in Figure 3a, a lytic activity was observed against patient's leukemic cells using unstimulated BM-infiltrating LGLs, and to a lesser extent using unstimulated PB LGLs. We further assessed the cytotolytic activity of LGL against ‘normal’ autologous BM cells obtained after the patient had undergone CR. As shown in Figure 3b, a significant – although very significantly lower – cytotoxicity was observed both with PB and BM LGLs.

LGLs do not express NK inhibitory receptor but express the 2B4 co-activating receptor whose ligand CD48 is expressed by the autologous acute myeloid leukemia cells (Figure 4)

Figure 4
figure4

Flow cytometry analysis of LGLs (upper rows) and leukemia blasts (lower row). Blank areas correspond to isotype-matched negative controls.

The two upper rows show the phenotype of LGLs (that was the same, for the markers analyzed here, after or before culture in IL-2, data not shown). These lymphocytes had a CD3+/CD56+/CD4CD8+/TcRαβ+ phenotype (first row), and we verified these cells were TcRγδ negative to eliminate the possibility of a cross-reactivity of the anti-TcRαβ mAb we used with TcRγδ (data not shown). The use of a panel of mAbs specific for different Vβ indicated that the LGL expansion consisted of polyclonal T cells (data not shown). These LGLs did not express the NK cells inhibitory receptors CD94/NKG2A (second row, second column), LIR-1 (second row, fourth column) or p58, p70, p140 (data not shown). We failed to detect the expression of the NK activating receptors NKG2C (second row, third column), NKp46 (second row, fifth column), NKp44 or NKp30 (data not shown). We detected high-level expression of the activatory NKG2D (data not shown) and 2B4 (second row, first column) molecules. We then performed the phenotypic analysis of leukemic blasts (Figure 4, lower row), which were CD34/CD13+/CD33+ and expressed MHC class I molecules. Interestingly, most leukemic cells expressed the CD48 molecule at high levels, which is the 2B4 ligand. The AML blasts did not express the NKG2D ligand MICA, as demonstrated by the use of a specific mAb (data not shown) or mRNA expression by RT-PCR analysis (not shown).

Cytotoxicity of cultured peripheral blood LGLs relies on the 2B4 triggering molecule (Figure 5)

Figure 5
figure5

Cytolytic activity of the patient's LGLs and function of 2B4. Panel a shows the cytotoxic activity of LGLs to lyse autologous leukemic cells and the effects of masking MHC class I or 2B4 by the use of specific mAbs of IgM subclass. Panel b shows the cytotoxicity of LGLs against the P815 cell line and the effects of 2B4 or CD3 cross-linking on target cell surface using IgG mAbs. Panel c shows the cytotoxicity of allogeneic NK cells against patient's leukemic blasts with the effects of 2B4 or MHC class I masking by specific mAbs.

In order to obtain a sufficient number of LGLs for repeated cytotoxicity experiments, LGL expansion was performed by short-term (1 week) culture in IL-2. Neither the expression of NK receptors nor the Vβ repertoire were modified by this culture (data not shown). As shown in Figure 5a, a significant spontaneous cytotoxicity against autologous leukemic cells was detected which was not modified by mAb masking of MHC class I molecules. In contrast, mAb masking of the 2B4 receptor (+/− masking of its ligand CD48) significantly reduced killing of leukemic target cells. This suggested that the 2B4 receptor was responsible for the induction of LGL-mediated cytotoxicity against the CD48+ LGL target cells. To confirm the possible triggering capability of the 2B4 molecules expressed on the patient's LGLs, we performed redirected killing experiments against P815 murine target cells (Figure 5b). In normal controls (ie CD3+/CD8+/2B4+ T cells derived from healthy individuals) the anti-2B4 mAb does not induce triggering of cytotoxicity (data not shown). In contrast, using the patient's LGLs under the same experimental conditions, triggering of the 2B4 molecule by an activating specific monoclonal antibody strongly induced killing of the P815 target (Figure 5b, filled squares). Notably, the magnitude of this activating effect was comparable to that detected in the presence of anti-CD3 mAb (Figure 5b, filled triangles). Finally, the patient's leukemic cells were used as targets for cytotoxicity mediated by allogeneic NK cells obtained from two different normal donors (Figure 5c). Allogeneic NK polyclonal cells hardly spontaneously killed leukemic target cells. On the other hand, in sharp contrast to the autologous setting, they displayed strong cytotoxicity in the presence of a masking anti-MHC class I monoclonal antibody.

Discussion

The 2B4-positive CD3+/CD56+/CD8+αβ T cell population represents a quite rare phenotype17 that was drastically expanded in our patient. The mechanisms leading to this expansion are under investigation and could directly involve leukemic cells via cytokine secretion such as IL-12,25 CD28 interactions with the ligands of the B7 family26 or triggering of other activation molecules such as 2B4.18 The analysis of the killing mechanism used by the patient's LGLs indicated that it did not correspond to ‘classical’ MHC-restricted antigen-specific lysis mediated by cytotoxic T lymphocytes, despite the CD3+/CD56+ phenotype of these LGLs. Indeed, masking of MHC class I molecules did not decrease cytotoxicity. Nonetheless, the cytotoxicity mechanism does not fit with classical NK cytotoxicity, since killing was not, on the contrary, increased by MHC class I molecule masking. Since the LGLs, as most CD8+αβ T cells, expressed the NK triggering receptor NKG2D, we questioned its role in our system. An anti-NKG2D blocking mAb (kindly provided by Dr D Pende, UO Immunologia, Istituto Scientifica Tumori, Genova, Italy) did not modify the killing of leukemic blasts by normal NK cells (not shown). Moreover, the AML blasts did not express the NKG2D ligand MICA, as demonstrated by the use of a specific mAb or mRNA expression by RT-PCR analysis (not shown). Finally, AML blasts are unlikely to express NKG2D ligand since these molecules have been mainly detected in cells of epithelial but not of hematopoietic origin.27,28,29,30 We then focused our attention on another NK activation molecule, 2B4, which was also expressed by the LGLs. From activation and masking experiments, we deduced that LGL's cytotoxicity at least partly relied on the co-stimulatory molecule 2B4. In our case, LGLs did not express the NK inhibitory receptors that counterbalance 2B4 activating properties and can inhibit the anti-tumor activity of T lymphocytes.31,32 That probably allowed the direct triggering via 2B4 molecule alone, in the absence of the known 2B4 co-activator receptors (ie the NCRs), which were not expressed by the LGLs. We nonetheless cannot exclude the hypothesis that the 2B4-dependent T cell activation may have occurred because of the simultaneous co-engagement of a still undefined receptor whose ligand was expressed on leukemic cells. Moreover, since the antibodies blocking the 2B4 activation pathway (anti-2B4, anti-CD48) only decreased the cell lysis to 50%, an additional unidentified pathway may also be involved. The 2B4-dependent cytotoxicity against PB or BM cells makes sense since the 2B4 ligand, ie the CD48 molecule, has a wide distribution in the hematopoietic system.33,34 This wide expression of CD48 may also account for the capacity of autologous LGLs to kill normal BM hemopoietic cells and could, at least partially, explain why in this patient pancytopenia paralleled LGL proliferation. Interestingly, this 2B4-mediated cytotoxicity is a novel mechanism of killing in humans. Indeed, an activating role for 2B4 in T cell killing was previously described in mice18,35 while, in contrast, 2B4 triggering has no effect on human T lymphocyte-mediated cytotoxicity.20,36,37

Our data, together with recent publications,3,17 suggest that the 2B4-positive CD3+/CD8+/CD56+ T lymphocyte subset selective expansion could be of interest in leukemia immunotherapy. The relevance of this particular T lymphocyte subpopulation is under investigation in a larger series of patients with hematological or solid organ malignancies.

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Acknowledgements

Research grant support from Groupement Entreprise Français Lutte Cancer, Association pour la Recherche contre le Cancer, Ligue contre le Cancer de Bastia, Fédération Nationale des Centres de Lutte Contre le Cancer, Fondation Contre la Leucémie, European Association for Cancer Research, Fondation pour la Recherche Médicale, Société Française contre le Cancer.

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Costello, R., Sivori, S., Mallet, F. et al. A novel mechanism of antitumor response involving the expansion of CD3+/CD56+ large granular lymphocytes triggered by a tumor-expressed activating ligand. Leukemia 16, 855–860 (2002). https://doi.org/10.1038/sj.leu.2402488

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Keywords

  • anti-tumor immune response
  • large granular lymphocytes
  • leukemia
  • natural killer receptors

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