High PD-L1 Expression in HRS Cells and Macrophages in Tumor Immune Microenvironment Is Associated with Adverse Outcome and EBV Positivity in Classical Hodgkin Lymphoma
Abstract
1. Introduction
2. Results
2.1. Association of PD-L1 Expression on HRS Cells with Clinical and Pathological Variables and Outcome of Classical Hodgkin Lymphoma
2.2. Association of PD-L1 Expression on Macrophages with Clinical and Pathological Variables and Outcome of Classical Hodgkin Lymphoma
3. Discussion
4. Materials and Methods
4.1. Patient Characteristics
4.2. Methods
4.2.1. Analysis of PD-L1 in HRS Cells
4.2.2. Analysis of PD-L1 in Macrophages
4.3. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
PD-L1 | Programmed Death-Ligand 1 |
HRS | Hodgkin and Reed–Sternberg |
cHL | Classical Hodgkin Lymphoma |
TME | Tumor Immune Microenvironment |
OS | Overall Survival |
PFS | Progression-Free Survival |
EBV | Epstein–Barr Virus |
H-score | Histologic Score |
CR | Complete Remission |
IFN-γ | Interferon Gamma |
PD-1 | Programmed Cell Death 1 |
ICIs | Checkpoint Inhibitors |
R/R | Relapsed/Refractory |
IQR | Interquartile Range |
MΦ | Macrophages |
EBER | Epstein–Barr Virus-Encoded RNA |
CI | Confidence Interval |
ANOVA | Analysis of Variance |
PET-CT | Positron Emission Tomography–Computed Tomography |
ER | Evidence Ratio |
CROHEM | Croatian Cooperative Group for Hematologic Diseases |
NCCN | National Comprehensive Cancer Network |
ABVD | Chemotherapy protocol: Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine |
BEACOPP | Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone |
OEPA | Vincristine, Etoposide, Prednisone, and doxorubicin |
DHAP | Cisplatin, Cytarabine, and Dexamethasone |
ICE | Ifosfamide, Carboplatin, and Etoposide |
ISH | In Situ Hybridization |
DAB | 3,3’-diaminobenzidine |
IHC | Immunohistochemistry |
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Variables | Median, IQR |
---|---|
PD-L1+ HRS H-score | 80 (36.5–142.8) |
Macrophages | 6.8 (5.3–8.9) |
PD-L1+ macrophages | 5.4 (3.6–7.1) |
Proportion of PD-L1+ macrophages (%) | 85.9 (65.4–91.9) |
Variable | PD-L1 H-Score | IQR of H-Score | p |
---|---|---|---|
Histological subtype | 0.10 | ||
Nodular sclerosis (n = 73) | 83 | 40–50 | |
Mixed cellularity (n = 21) | 75 | 31–121 | |
Lymphocyte-rich (n = 3) | 20 | 3–80 | |
Lymphocyte-depleted (n = 1) | 216 | 216–216 | |
Clinical stage | 0.28 | ||
Early favorable (n = 23) | 81 | 25–145 | |
Early unfavorable (n = 29) | 67 | 35–118 | |
Advanced (n = 45) | 85 | 40–190 | |
Extranodal disease | 0.35 | ||
no (n = 66) | 84 | 40–154 | |
yes (n = 30) | 77 | 33–142 | |
Bulky disease | 0.69 | ||
no (n = 72) | 82 | 28–133 | |
yes (n = 26) | 80 | 38–145 | |
B symptoms | 0.42 | ||
no | 75 | 36–143.5 | |
yes | 85 | 37.5–143.5 | |
EBV status | 0.005 | ||
no (n = 75) | 70 | 34–104 | |
yes (n = 22) | 136 | 82.5–182.3 |
Variable | Macrophages | PD-L1+ Macrophages | Proportion of PD-L1+ Macrophages | |||||
---|---|---|---|---|---|---|---|---|
Subtype | N | IQR | N | IQR | % | IQR | ||
Nodular sclerosis | 6.3 | 4.65–7.73 | 4.9 | 3.21–6.65 | 85.3 | 63.3–91.2 | ||
Mixed cellularity | 9.6 | 7.62–10.65 | 8.0 | 6.4–10.31 | 89.8 | 83.9–93.9 | ||
Lymphocyte-rich | 5.2 | 4.3–6.7 | 4.2 | 1.4–4.6 | 68.7 | 32.6–80.8 | ||
Lymphocyte-depleted | 8.7 | 8.7–8.7 | 4.6 | 4.6–4.6 | 52.9 | 52.9–52.9 | ||
p | 0.0002 | <0.0001 | 0.02 | |||||
Extranodal | ||||||||
no | 6.65 | 4.92–7.92 | 5.0 | 3.21–6.8 | 85.1 | 63.1–90.2 | ||
yes | 7.48 | 5.3–9.8 | 6.3 | 4.0–8.42 | 88.7 | 76.7–94.9 | ||
p | 0.18 | 0.05 | 0.06 | |||||
Bulky | ||||||||
no | 7.35 | 5.3–9.2 | 5.75 | 4.0–8.0 | 87.1 | 74.4–92.0 | ||
yes | 6.2 | 4.1–7.78 | 3.9 | 2.87–6.4 | 82.3 | 56.2–91.7 | ||
p | 0.07 | 0.04 | 0.04 | |||||
EBV status | ||||||||
negative | 6.3 | 4.6–7.8 | 4.8 | 3.3–6.8 | 84 | 64.1–90.9 | ||
positive | 8.3 | 6.9–9.8 | 6.8 | 5.6–8.9 | 90.7 | 82.2 –94.6 | ||
p | 0.008 | 0.005 | 0.11 |
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Miljak, A.; Pavlović, A.; Benzon, B.; Čutura, L.V.; Galušić, D.; Vujčić, M.; Blaslov, V.; Durdov, M.G. High PD-L1 Expression in HRS Cells and Macrophages in Tumor Immune Microenvironment Is Associated with Adverse Outcome and EBV Positivity in Classical Hodgkin Lymphoma. Int. J. Mol. Sci. 2025, 26, 5592. https://doi.org/10.3390/ijms26125592
Miljak A, Pavlović A, Benzon B, Čutura LV, Galušić D, Vujčić M, Blaslov V, Durdov MG. High PD-L1 Expression in HRS Cells and Macrophages in Tumor Immune Microenvironment Is Associated with Adverse Outcome and EBV Positivity in Classical Hodgkin Lymphoma. International Journal of Molecular Sciences. 2025; 26(12):5592. https://doi.org/10.3390/ijms26125592
Chicago/Turabian StyleMiljak, Antonija, Antonia Pavlović, Benjamin Benzon, Lučana Vicelić Čutura, Davor Galušić, Milan Vujčić, Viktor Blaslov, and Merica Glavina Durdov. 2025. "High PD-L1 Expression in HRS Cells and Macrophages in Tumor Immune Microenvironment Is Associated with Adverse Outcome and EBV Positivity in Classical Hodgkin Lymphoma" International Journal of Molecular Sciences 26, no. 12: 5592. https://doi.org/10.3390/ijms26125592
APA StyleMiljak, A., Pavlović, A., Benzon, B., Čutura, L. V., Galušić, D., Vujčić, M., Blaslov, V., & Durdov, M. G. (2025). High PD-L1 Expression in HRS Cells and Macrophages in Tumor Immune Microenvironment Is Associated with Adverse Outcome and EBV Positivity in Classical Hodgkin Lymphoma. International Journal of Molecular Sciences, 26(12), 5592. https://doi.org/10.3390/ijms26125592