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Keywords:

  • B7-2;
  • co-stimulatory molecule;
  • acute leukaemia;
  • prognosis;
  • tumour immunity

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

We examined the expression of co-stimulatory molecules on leukaemic cells of 52 adult patients with acute myeloid leukaemia (AML) (34 men and 18 women) and analysed the relationship between these expressions and the patient's prognosis. B7-1 was not expressed in any of the 23 patients investigated, whereas B7-2 was expressed in 26/52 patients (50.0%). B7-2 was expressed in all AML patients with monocytic morphology (M4 or M5) and in 16/42 cases without monocytic morphology. CD54 was expressed in 28/37 patients examined (75.7%), and CD58 was expressed in all of the AML patients except one (M7). The overall survival of the 26 B7-2-positive leukaemia patients (1–24 months, median survival 11.5 months) was significantly shorter than that of the 26 B7-2-negative leukaemia patients (1–71+ months, median 35.1 months) (P = 0.0080). In addition, the B7-2-positive patients exhibited significantly shorter disease-free survival periods compared to the B7-2-negative patients (P = 0.021). There was no significant difference in age, sex, haematological data and complete remission rate between the B7-2-positive and B7-2-negative patients. Our results indicated that B7-2 is one of the most crucial factors in the prognosis of adult acute leukaemia and can be expected to have an important role in tumour immunity.

With recent advances in combination chemotherapy, approximately 60–80% of patients with adult acute leukaemia achieve complete remission (CR). However, only about half of the CR achievers remain leukaemia free ( Hoelzer et al, 1996 ; Ohno et al, 1993 ). What factors determine whether such patients will relapse or not are unclear, but it has been suggested that the induction of efficient anti-tumour immunity will play a critical role in achieving a cure for this disease. Various cell-mediated immune systems such as cytotoxic T lymphocytes (CTL), lymphokine-activated killer (LAK) cells ( Archimbaud et al, 1991, 1992; Lauria et al, 1994 ) and activated macrophages ( Kakita et al, 1989 ; Nakabo et al, 1993 ) have been reported to be involved in the immune surveillance against leukaemia. Among them, the CTL seem to play a central role.

Recent studies demonstrated that a co-stimulatory signal, in addition to the signal from a T-cell receptor, is required for the full activation of T cells ( Jenkins et al, 1991 ; June et al, 1990 ; Ledbetter et al, 1990 ) and for the generation of CTL fully active against tumour cells ( Chen et al, 1992 ; Schwartz, 1992). Such a co-stimulatory signal is introduced through surface molecules on T cells such as CD28, leucocyte-function-associated antigen-1 (LFA-1) ( Van Seventer et al, 1990 ), CD2 ( Koyasu et al, 1990 ) and others. Among these, CD28 has been shown to be the main positive regulator of T-cell responses. The major ligands for CD28 are B7-1 (CD80) ( Gimmi et al, 1991 ; Linsley et al, 1990 ) and B7-2 (CD86) ( Azuma et al, 1993 ; Freeman et al, 1993 ). B7 molecules provide positive signals through CD28 and negative signals through CTLA-4 for T cells ( Krummel & Allison, 1995).

It is possible that leukaemic cells express B7 molecules themselves, since B7-1 is present on activated lymphocytes and monocytes ( Yokochi et al, 1982 ; Freedman et al, 1991 ) and B7-2 is present on activated lymphocytes and resting monocytes ( Azuma et al, 1993 ). A very important issue is whether leukaemia cells with a spontaneous expression of B7 molecules have a positive or negative effect on anti-tumour immunity in vivo.

In this study we examined the relationship between the expression of co-stimulatory molecules such as B7-1, B7-2, CD54 (a ligand for LFA-1) and CD58 (a ligand for CD2) on the leukaemic cells of patients with acute myeloid leukaemia (AML) and their prognosis. We found that the patients with B7-2-positive AML had much poorer prognoses compared with the patients with B7-2-negative AML. Our results strongly suggested that B7-2 is a crucial predictor of prognosis in adult AML.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

Patients

52 newly diagnosed adult patients (34 men and 18 women) with acute myeloid leukaemia seen in our department between June 1988 and January 1997 were examined. All patients gave their informed consent for the procedures involved. The diagnosis was based on May-Giemsa-stained bone marrow smears and cytochemistry, according to the French–American–British (FAB) group criteria. No patient had a record of prior myelodysplastic syndrome, nor a history of other pre-existing haematological abnormalities.

All patients were treated by intensive combination chemotherapy (Japan Adult Leukemia Study Group (JALSG) protocol) ( Ohno et al, 1993 ). The induction therapy was given according to a response-oriented individualized therapy that consisted of behenoyl cytarabine (BH-AC, 200 mg/m2), 6-mercaptopurine (6MP, 70 mg/m2 with 300 mg/d of allopurinol), prednisolone (PSL, 40 mg/m2), and daunorubicin (DNR, 40 mg/m2). For AML-M3, all-trans retinoic acid was used in combination with the chemotherapy. If patients did not achieve CR after the first course, the same therapy was repeated once more after a 3–4-week interval. After achieving CR, patients received three courses of intensive consolidation chemotherapy consisted of BDMP (BH-AC, DNR, 6MP, PSL), MAP (mitoxantrone (MIT), cytarabine (Ara-C), PSL), and BEVP (BH-AC, etoposide (ETP), vindesine (VDS), PSL). Intensification and maintenance therapy followed the consolidation therapy.

Immunological phenotyping of leukaemic cells

Mononuclear cells were isolated from heparinized bone marrow or peripheral blood on Percoll gradients. All samples contained at least 80% blasts. In 12 cases an analysis of surface antigens of the cells was performed with fresh samples obtained before the induction chemotherapy was administered. In other cases an immunological study was performed with the cells that were obtained before chemotherapy and cryopreserved in RPMI 1640 medium with 20% heat-inactivated fetal calf serum and 10% dimethyl-sulphoxide. By comparing the expression of surface antigens of the 12 fresh samples before and after cryopreservation it was ascertained that the expressions of B7-1, B7-2, CD54, CD58 on the cell were not affected by the cryopreservation and thawing of the cells.

Human AB serum was first added to the cell suspension to avoid non-specific binding of the monoclonal antibody (MoAb) on Fc receptors. Then, 1 × 106 cells were incubated at 4°C for 30 min with the MoAbs at saturation concentrations and washed twice with phosphate-buffered saline (PBS) containing 0.1% azide and 0.1% bovine serum albumin (BSA). For the non-conjugated antibody, cells were further incubated for 30 min at 4°C with a phycoerythrin (PE)-conjugated goat anti-mouse immunoglobulin (DAKO, Kyoto, Japan).

The MoAbs used were as follows: PE-conjugated anti-CD80 (anti-BB1/B7, clone L307.4), anti-CD54 (Leu-54, clone LB-2) and PE-conjugated anti-CD58 (anti-LFA-3, clone L306.4). These were purchased from Becton Dickinson (Tokyo, Japan). Anti-CD86 (BU 63) was purchased from Serotec (Oxford, U.K.).

PE-conjugated and non-conjugated mouse IgG1 (clone DAK-G01) for negative controls were purchased from DAKO. The analysis was performed on a FACS flow cytometer (Becton Dickinson). Samples were analysed after gating on the combination of forward light scatter and perpendicular light scatter to discriminate the blasts from other myeloid cells and debris. In two cases we performed two-colour staining with the above antibodies and FITC-conjugated anti-CD3 (clone SK7, Becton Dickinson) to discriminate the blasts from normal T cells. Samples were considered positive for a MoAb if > 20% of cells showed specific labelling above that of controls.

Statistical analysis

Survival curves were estimated using the Kaplan-Meier method, and the difference was evaluated by log-rank test. Differences in cellular and clinical characteristics between the B7-2-positive and B7-2-negative patients were evaluated by chi-squared statistics or Student's t-test.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

Expression of co-stimulatory molecules on leukaemic cells

As shown in Table I, B7-1 was expressed in none of the 23 patients examined, whereas B7-2 was expressed on leukaemic cells from 26/52 patients examined (50.0%). B7-2 was detected on all AML cells with monocytic morphology (M4 or M5) and in 16/42 patients with AML without apparent monocytic differentiation. We also examined the expression of other co-stimulatory molecules such as CD54 and CD58. CD54 was expressed on 28/37 patients' leukaemic cells (75.7%). CD58 was detected in all cases except one with megakaryocytic differentiation (M7).

Table 1.  Table I. Expression of co-stimulatory molecules on leukaemic cells of patients with acute myeloid leukaemia (AML). Thumbnail image of

Comparison of clinical and haematological characteristics between B7-2-positive and B7-2-negative AML patients

When the patient characteristics such as sex, age and haematological data between B7-2-positive and -negative patients were compared, there were no significant differences between the two groups ( Table II). In cytogenetic analysis, t(8;21) was observed in one B7-2 positive and two B7-2 negative patients, t(15;17) in three positive and three negative patients, and inv(16) in one positive patients. Chromosomal abnormalities other than these favourable types were observed in seven B7-2 positive and four B7-2 negative patients ( 2Table II).

Table 2.  Table II. Differences in clinical and haematological characteristics between B7-2-negative and B7-2- positive AML patients. Thumbnail image of
  • a

    N.S.: not significant. Karyotype (favourable abnormalities (t(8;21), t(15;17), inv(16))/other abnormalities/no abnormalities). Other abnormalities: (+8), (−7), (−16, −18,t(12,20) and others) and (−5,−7,+9 and others) in B7-2(−) (−9, −14, −16, −17 and others), (1p+, 10p+, 11q-,17q+), (−16, −17), (t(2;11)), (t(5;11)),(t(6;11)) and (add(17)) in B7-2(+).

  • Analysis of the prognosis of leukaemia patients in reference to B7-2 expression

    We analysed the relationship between the prognosis of AML patients and the expression of B7 molecules on their leukaemic cells.

    The 26 B7-2-positive patients exhibited significantly shorter survival compared to the 26 B7-2-negative patients (P = 0.0080) (Fig 1). The overall survival periods of the B7-2-positive and -negative AML patients were 1–24 months (median survival 11.5 months) and 1–71+ months (35.1 months), respectively.

    image

    Figure 1. Fig 1. Overall survival of acute myeloid leukaemia (AML) patients in reference to the cellular expression of B7-2. The overall survival of the B7-2-positive leukaemia patients (n = 26) was significantly shorter than that of B7-2-negative leukaemia patients (n = 26) (P = 0.0080).

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    In contrast, the expression of B7-2 did not significantly affect the CR rate. 16/26 B7-2-positive patients and 20/26 B7-2-negative patients achieved CR. However, the B7-2-positive patients showed a markedly reduced remission duration. Among the 36 patients who achieved CR, the B7-2-positive patients exhibited significantly shorter disease-free survival periods compared to the B7-2-negative patients (P = 0.021) (Fig 2). The disease-free survival periods of the B7-2-positive and -negative AML patients were 1–23 months (10.8) and 3–66+ months (30.9), respectively.

    In contrast to B7-2, the expression of CD54 on AML cells was not significantly correlated with the survival of the patients (P = 0.48). The overall survival periods of the CD54-positive and -negative AML patients were 1–67+ months (23.2) and 1–71+ months (31.6), respectively.

    Prognostic implications of B7-2 expression on subsets of AML subtypes

    The expression of B7-2 was correlated with poorer prognosis even among the patients with AML with a non-monocytic phenotype. Such B7-2-positive patients (13/34 AML (M1 + M2)) showed significantly shorter survival compared with the B7-2-negative patients (P = 0.0088) (Fig 3). The overall survival periods of the B7-2-positive and -negative AML (M1+M2) patients were 2–22 months (12.0) and 2–71+ months (41.8), respectively. In addition, the B7-2-positive AML (M1+M2) patients exhibited significantly shorter disease-free survival than the B7-2-negative patients (P = 0.019) (Fig 4). The disease-free survival periods of the B7-2-positive and -negative AML (M1+M2) patients were 1–21 months (9.5) and 3–66+ months (35.2), respectively.

    image

    Figure 3. ) was significantly shorter than that of the B7-2-negative AML (M1 + M2) patients (n = 21) (P = 0.0088).

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    image

    Figure 4. Fig 4. Disease-free survival of AML (M1 + M2) patients in reference to the cellular expression of B7-2. The disease-free survival of the B7-2-positive AML (M1 + M2) patients (n = 8) was significantly shorter than that of the B7-2-negative AML (M1 + M2) patients (n = 17) (P = 0.019).

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    DISCUSSION

    1. Top of page
    2. Abstract
    3. MATERIALS AND METHODS
    4. RESULTS
    5. DISCUSSION
    6. References

    In the present study B7-2-positive AML patients showed significantly shorter survival compared to the B7-2-negative patients. The disease-free survival periods of B7-2-positive AML patients were significantly shorter than those of the B7-2-negative patients. This is in contrast to many studies demonstrating the important role of B7 molecules in tumour rejection in experimental animals ( Townsend & Allison, 1993; Dunussi Joannopoulos et al, 1996 ; Matulonis et al, 1996 ). However, immune response of the host against tumour cells exogenously introduced B7 molecules may not be equivalent to that against tumour cells with endogenous B7.

    Why is the prognosis of B7-2-positive leukaemia patients poor? Differences in the type of leukaemia were not crucial to our findings, since the analysis of the patients whose type of leukaemia is limited to M1 and M2 still showed that the B7-2-positive patients had a shorter survival than those who were B7-2-negative. It is also unlikely that our findings resulted from the deviation of other prognostic factors that have been documented in the studies of acute leukaemia ( Hoelzer et al, 1996 ; Ohno et al, 1993 ), since there was no significant difference in age, WBC count, haemoglobin value or karyotype between the B7-2-positive and -negative patients. The rate of CR of two groups also had no significant difference in this study.

    There are several possible explanations for the poor prognosis of B7-2-positive leukaemia patients. B7-2-positive leukaemia cells may not exhibit tumour antigenicity, so that they evade tumour immunity despite the expression of co-stimulatory molecules. In fact, Chen et al (1994 ) showed that tumour immunogenicity was critical to the outcome of the B7 co-stimulation of T-cell-mediated tumour immunity by demonstrating the failure of rejection of B7-transfected nonimmunogenic tumours in experimental animals. The absence of tumour antigenicity may be caused by the abnormalities of major histocompatibility complex (MHC) molecules or the absence of tumour antigen peptides in the groove of MHC molecules secondary to defective antigen processing. Other potential obstacles that result in defective antigen presentation by B7-2-positive leukaemias include the expression of down-regulatory molecules and suppressive cytokines by leukaemic cells. Furthermore, other factors relevant to patient survival should be considered such as stroma cell interaction and drug resistance patterns of these leukaemic cells.

    Alternatively, B7 molecules modulate the balance of Th1 and Th2 ( Kuchroo et al, 1995 ; Matulonis et al, 1996 ). Kuchroo et al (1995 ) have shown that B7-2 co-stimulation resulted in the development of Th2 in experimental animal systems. Th2 predominancy seems to be disadvantageous in tumour immunity ( Mosmann & Coffman, 1989; Powrie & Coffman, 1993). Another interesting possibility is the B7 interaction with CTLA-4, which has been shown to deliver inhibitory signals for T-cell activation ( Krummel & Allison, 1995). There are few CTLA-4 molecules on resting T cells, so the major ligand for B7 molecules in the initiation of T-cell activation is CD28. After the activation of T cells, surface CTLA-4 molecules increase in number and become the major ligand for B7 molecules because CTLA-4 binds both B7 molecules with an affinity 20-fold higher than that of CD28. B7 ligation of CTLA-4 delivers inhibitory signals for T-cell activation and terminates the T-cell response. Such inhibitory molecules on T cells activated by B7-2 on leukaemic cells may down-regulate the anti-leukaemic immune responses in the patients.

    Further studies on the antigenicity of B7-2-positive leukaemic cells, intracellular signalling from B7-2 in leukaemic cells and T-cell functions in patients with B7-2-positive leukaemia will provide important information in the analysis of the pathophysiology of acute leukaemia and in the search for successful immunotherapy against leukaemia.

    References

    1. Top of page
    2. Abstract
    3. MATERIALS AND METHODS
    4. RESULTS
    5. DISCUSSION
    6. References
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