High M-MDSC Percentage as a Negative Prognostic Factor in Chronic Lymphocytic Leukaemia
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. The Percentage of M-MDSC Is Increased in the Peripheral Blood of CLL Patients and Correlates with The Rai Stage
2.2. M-MDSC Percentage Is Higher in Patients from High-Risk Groups
2.3. High M-MDSC Percentage Is a Negative Prognostic Marker for Time-to-Treatment and Survival Time
2.4. IDO, ARG1, NOS2, IL-10, and TGF-Β1 Are Overexpressed by CLL-Derived M-MDSC
2.5. The CD3 Ζ Chain (CD247) Expression in T Lymphocytes Is Significantly Lower in the M-MDSChigh Group
3. Discussion
4. Materials and Methods
4.1. Patients and Samples
4.2. Detection of M-MDSC
4.3. Analysis of Intracellular IDO, Arg1, NOS2, IL-10, or TGF-Β1 Expressions
4.4. Flow Cytometry Analysis of M-MDSC
4.5. Flow Cytometry Sorting of M-MDSC Cells For Reverse Transcription-Quantitative Polymerase Chain Reaction (RT-Qpcr)
4.6. RNA Preparation and RT-Qpcr for IDO, ARG1, NOS2, IL-10, and TGF-Β1
4.7. The CD3 Ζ Chain (CD247) Analysis in T Lymphocytes
4.8. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Variable | All Patients | M-MDSClow | M-MDSChigh |
---|---|---|---|
No. of patients (%) | 110 | 56 (50.1) | 54 (49.9) |
Sex | |||
Female (%) | 60 (51.8) | 26 (46.4) | 34 (63.0) |
Male (%) | 50 (48.2) | 30 (53.6) | 20 (37.0) |
Rai Stage | |||
0 (%) | 56 (50.9) | 33 (58.9) | 23 (42.6) |
I (%) | 25 (22.7) | 15 (26.8) | 10 (18.5) |
II (%) | 17 (15.5) | 6 (10.7) | 11 (20.4) |
III (%) | 7 (6.4) | 1 (1.8) | 6 (11.1) |
IV (%) | 5 (4.5) | 1 (1.8) | 4 (7.4) |
ZAP-70 (cut-off 20%) | |||
Positive (%) | 38 (34.5) | 15 (26.8) | 23 (42.6) |
Negative (%) | 72 (65.5) | 41 (73.2) | 31 (57.4) |
CD38 (cut-off 30%) | |||
Positive (%) | 37 (33.6) | 14 (55.3) | 23(24.6) |
Negative (%) | 73 (66.4) | 42 (44.7) | 31 (75.4) |
IGHV gene mutation status | |||
Mutated (%) | 26 (23.6) | 17 (30.4) | 9 (16.7) |
Unmutated (%) | 19 (17.3) | 6 (10.7) | 13 (24.1) |
Not available (%) | 65 (59.1) | 33 (58.9) | 32 (59.2) |
Cytogenetic abnormalities | |||
del(17p13.1) (%) | 5 (4.5) | 4 (7.1) | 1 (1.9) |
del(11q22.3) (%) | 14 (12.7) | 5 (8.9) | 9 (16.6) |
del(17p13.1) and del(11q22.3) (%) | 2 (1.8) | 1 (1.8) | 1 (1.9) |
Without del(17p13.1) and del(11q22.3) (%) | 89 (81.0) | 46 (82.2) | 43 (79.6) |
Patients requiring therapy (%) | 26 (23.6) | 7 (12.5) | 19 (35.2) |
Untreated patients (%) | 84 (76.4) | 49 (87.5) | 35 (34.8) |
No. of Deaths (%) | 8 (7.3) | 1 (1.8) | 7 (12.9) |
Age at diagnosis (years) * | 65 (47–87) | 66 (48–87) | 64 (47–85) |
WBC count (G/L) * | 23.9 (10.1–298.4) | 20.79 (10.72–26.8) a | 27.11 (10.1–298.4) a |
Lymphocyte count (G/L) * | 17.86 (5.2–284.9) | 16.39 (5.2–53.5) b | 22.7 (5.5–284.9) b |
LDH (IU/L) * | 366 (178–618) | 366 (246–618) | 368 (178–579) |
Haemoglobin (g/dL) * | 13.9 (8.1–17.2) | 14.0 (11.4–17.2) | 13.8 (8.1–16.2) |
Platelets (G/L) * | 191 (49–414) | 198 (90–414) | 182 (142–394) |
β2M (mg/dL) * | 2.4 (1.3–5.4) | 2.26 (1.4–4.2) | 2.59 (1.3–5.4) |
% CD19+/CD5+/ZAP-70+ cells * | 13.2 (0.2–50.3) | 11.97 (0.37–44.3) | 14.5 (0.2–50.3) |
% CD19+/CD5+/CD38+ cells * | 6.9 (0.2–88.7) | 4.99 (0.2–88.7) | 9.38 (0.2–80.9) |
Variations | Univariate # | Multivariate | |||
---|---|---|---|---|---|
Median TTT (months) | HR (95% CI) | p | HR (95% CI) | p | |
Age | |||||
≥65 years | 29 | 0.77 (0.35–1.70) | 0.525 | ||
<65 years | 34 | ||||
ZAP-70 | |||||
≥20% | 21 | 5.76 (2.48–13.38) | <0.0001 | 3.88 (1.43–10.47) | <0.01 |
<20% | 35 | ||||
CD38 | |||||
≥30% | 20 | 4.53 (1.99–10.30) | <0.01 | 1.64 (0.60–4.50) | 0.333 |
<30% | 34 | ||||
Β2M | |||||
≥3.5 mg/dL | 15 | 4.96 (2.24–10.97) | <0.0001 | 4.29 (2.01–11.16) | 0.085 |
<3.5 mg/dL | 36 | ||||
del(17p13.1) or del(11q22.3) | |||||
Positive | 20 | 3.22 (1.44–7.19) | <0.01 | 2.59 (1.12–6.02) | <0.05 |
Negative | 32 | ||||
LDH | |||||
≥ULN * | 29 | 2.29 (1.10–4.76) | 0.155 | ||
<ULN | 34 | ||||
IGHV mutation status# | |||||
Unmutated | 40 | 4.04 (1.27–12.80) | 0.056 | ||
Mutated | 44 | ||||
M-MDSC | |||||
≥9.35% | 26 | 0.31 (0.13–0.72) | <0.01 | 0.39 (0.16–0.96) | <0.05 |
<9.35% | 40 |
Variations | Univariate # | Multivariate | |||
---|---|---|---|---|---|
Median OS (months) | HR (95% CI) | p | HR (95% CI) | p | |
≥65 years | 36 | 1.46 (0.34–6.13) | 0.603 | ||
<65 years | 40 | ||||
ZAP-70 | |||||
≥20% | 35 | 1.21 (0.28–5.05) | <0.01 | 0.39 (0.08–1.83) | 0.238 |
<20% | 41 | ||||
CD38 | |||||
≥30% | 37 | 2.00 (0.50–8.01) | 0.326 | ||
<30% | 38 | ||||
Β2M | |||||
≥3.5 mg/dL | 31 | 10.26 (2.06–50.89) | <0.01 | 10.36 (1.85–58.20) | <0.01 |
<3.5 mg/dL | 40 | ||||
del(17p13.1) or del(11q22.3) | |||||
Positive | 33 | 4.15 (1.04–16.63) | <0.01 | 3.35 (0.82–13.80) | 0.092 |
Negative | 43 | ||||
LDH | |||||
≥ULN * | 32 | 0.41 (0.09–1.73) | 0.22 | ||
<ULN | 41 | ||||
M-MDSC | |||||
≥9.35% | 33 | 0.22 (0.05–0.86) | <0.05 | 0.18 (0.02–1.44) | 0.107 |
<9.35% | 45 |
Variable | Unit | HV (n = 20) Median (IQR) | CLL (n = 60) Median (IQR) | p |
---|---|---|---|---|
IDO | % | 2.32 (1.40–4.42) | 60.51 (19.77–79.46) | <0.0001 |
ΔMFI | 214.6 (167.9–329.6) | 350.0 (295.6–475.3) | <0.05 | |
Arg1 | % | 51.69 (16.36–65.33) | 86.19 (70.64-99.43) | <0.0001 |
ΔMFI | 359.8 (317.4–597.9) | 608.5 (390.7–770.6) | <0.05 | |
NOS2 | % | 21.64 (12.23–42.30) | 70.77 (47.04–92.08) | <0.0001 |
ΔMFI | 255.7 (199.1–319.7) | 468.0 (215.8–655.7) | <0.01 | |
IL-10 | % | 0.66 (0.12–1.64) | 27.34 (16.3–71.03) | <0.0001 |
ΔMFI | 275.3 (195.2–323.6) | 390.0 (328.1–477.5) | <0.01 | |
TGF-β | % | 1.44 (0.70–4.64) | 49.93 (22.17–81.29) | <0.0001 |
ΔMFI | 326.2 (229.0–397.7) | 430.3 (332.3–553.5) | <0.01 |
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Zarobkiewicz, M.; Kowalska, W.; Chocholska, S.; Tomczak, W.; Szymańska, A.; Morawska, I.; Wojciechowska, A.; Bojarska-Junak, A. High M-MDSC Percentage as a Negative Prognostic Factor in Chronic Lymphocytic Leukaemia. Cancers 2020, 12, 2614. https://doi.org/10.3390/cancers12092614
Zarobkiewicz M, Kowalska W, Chocholska S, Tomczak W, Szymańska A, Morawska I, Wojciechowska A, Bojarska-Junak A. High M-MDSC Percentage as a Negative Prognostic Factor in Chronic Lymphocytic Leukaemia. Cancers. 2020; 12(9):2614. https://doi.org/10.3390/cancers12092614
Chicago/Turabian StyleZarobkiewicz, Michał, Wioleta Kowalska, Sylwia Chocholska, Waldemar Tomczak, Agata Szymańska, Izabela Morawska, Agnieszka Wojciechowska, and Agnieszka Bojarska-Junak. 2020. "High M-MDSC Percentage as a Negative Prognostic Factor in Chronic Lymphocytic Leukaemia" Cancers 12, no. 9: 2614. https://doi.org/10.3390/cancers12092614