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Original Articles
Clinicopathological Significance of Tumor-Infiltrating T Lymphocytes and Macrophages in Primary Large B-Cell Lymphoma of Immune-Privileged Sites
Jinseong Kim, Deokhoon Kim, Hyungwoo Cho, Dok Hyun Yoon, Heounjeong Go
Received June 19, 2025  Accepted August 12, 2025  Published online August 13, 2025  
DOI: https://doi.org/10.4143/crt.2025.641    [Epub ahead of print]
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Immune-privileged large B-cell lymphomas (IP-LBCLs), comprising primary central nervous system lymphoma (PCNS-LBCL), primary vitreoretinal lymphoma (PVR-LBCL), and primary testicular lymphoma (PT-LBCL), originate in sites with limited immune surveillance. Owing to their rarity, the prognostic implications of the tumor microenvironment in IP-LBCLs remain unclear, warranting further investigation.
Materials and Methods
This study evaluated 109 IP-LBCL cases (PCNS-LBCL, n=87; PT-LBCL, n=22; six cases of PVR-LBCL excluded) using multiplex immunohistochemistry on tissue microarrays, along with clinicopathological analysis. Immune cell infiltration, tumor major histocompatibility complex (MHC) class I, and programmed death ligand-1 (PD-L1) expression, and their associations with clinical outcomes, were evaluated.
Results
PT-LBCL demonstrated higher infiltration of all tumor-infiltrating T lymphocyte (TIL) subsets than PCNS-LBCL (all p < 0.05). Elevated CD4+ and CD8+ T-cell levels correlated with prolonged progression-free survival (PFS) (both p < 0.05). M1 macrophage infiltration was associated with improved PFS (p=0.005) and independently predicted a favorable prognosis (hazard ratio, 0.49; p=0.041). Loss of MHC class I expression was more frequent in PT-LBCL than in PCNS-LBCL (77.3% vs. 9.2%, p < 0.001). TIL infiltration predicted improved PFS only when the tumor MHC class I was preserved. Moreover, programmed death protein-1 (PD-1)+ TILs and tumor PD-L1 expression were associated with prognosis in conjunction with various clinicopathological variables.
Conclusion
These findings highlight the favorable prognostic role of TILs and M1 macrophages, and underscore the complex immune–tumor interactions in IP-LBCLs, despite their origin in immune-privileged sites.

Citations

Citations to this article as recorded by  
  • The Landscape of Primary Central Nervous System Lymphoma (PCNSL): Clinicopathologic and Genomic Characteristics and Therapeutic Perspectives
    Huijuan Jiang, Lin Nong
    Cancers.2025; 17(17): 2909.     CrossRef
  • 1,497 View
  • 76 Download
  • 1 Crossref
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Hematologic malignancy
Pembrolizumab for Patients with Relapsed or Refractory Extranodal NK/T-Cell Lymphoma in Korea
Ji Yun Lee, Ji Hyun Kwon, Joon Young Hur, Jun Ho Yi, Ji Hyun Lee, Hyungwoo Cho, Young Rok Do, Jae-Cheol Jo, Hye Jin Kang, Yougil Koh, Won Sik Lee, Sung Nam Lim, Sang Eun Yoon, Seok Jin Kim, Jeong-Ok Lee
Cancer Res Treat. 2024;56(2):681-687.   Published online November 10, 2023
DOI: https://doi.org/10.4143/crt.2023.1042
AbstractAbstract PDFPubReaderePub
Purpose
Programmed death-1 blockade with pembrolizumab has shown promising activity in relapsed/refractory (R/R) extranodal natural killer/T-cell lymphoma (NKTCL), but studies are limited, with small patient numbers.
Materials and Methods
Thirteen institutes involved with the Consortium for Improving Survival of Lymphoma, a Korean lymphoma study group, collected the clinical data of 59 patients treated with pembrolizumab as salvage therapy between 2016 and 2022.
Results
The median age of the patients was 60 years (range, 22 to 87 years), and 76.3% had advanced Ann Abor stage disease. Pembrolizumab was given to 35.6%, 40.7%, and 23.7% of the patients as second-, third-, and fourth- or higher-line chemotherapy, respectively. The overall response rate was 40.7%, with 28.8% having complete response. The estimated 2-year progression-free survival (PFS) and overall survival rates for all patients were 21.5% and 28.7%, respectively; for responders, the rates were 53.0% and 60.7%, respectively. Although not statistically significant, Eastern Cooperative Oncology Group performance status ≥ 2 (hazard ratio [HR], 1.91; 95% confidence interval [95% CI], 0.93 to 3.94; p=0.078) and stage III or IV disease (HR, 2.59; 95% CI, 0.96 to 6.96; p=0.060) were associated with a trend toward shorter PFS in multivariate analysis. Grade 3 or 4 adverse events (AEs) were noted in 12 patients (20.3%); neutropenia (10.2%), fatigue (6.8%), and pneumonitis (5.1%) were most common AEs.
Conclusion
In conclusion, while pembrolizumab had a modest effect on patients with R/R NKTCL, it may be a useful salvage therapy for patients with localized disease and good performance status.

Citations

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  • Anti-PD-1 antibody combined with P-GEMOX chemotherapy versus P-GEMOX chemotherapy with or without autologous stem-cell transplantation for previously untreated advanced natural killer/T cell lymphoma: a retrospective cohort study
    Qihua Zou, Yi Cao, Liang Wang, Wuping Li, Qingsong Yin, Yudan Wu, Hongmei Jing, Zhigang Peng, Xiuhua Sun, Jun Rao, Ying Chen, Hongyu Zhang, Dongfeng Zeng, Bingzong Li, Ying Zhao, Xudong Zhang, Yuchen Zhang, Yan Gao, Bing Bai, Yi Xia, Yu Fang, Zouxiang Che
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    Yasuaki Harabuchi
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    Qihao Zhang, Xin Wang
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  • Outcomes With First‐Line PD1 Inhibitors in Extranodal NK/T‐Cell Lymphoma: A Comparative Analysis From a 755‐Patient Multicenter Cohort
    Hailing Liu, Mei Sun, Chunling Wang, Xiaoqiong Tang, Lixia Sheng, Jie Ma, Xuzhang Lu, Hongming Huang, Jinning Shi, Ran Li, Jing Zhang, Manling Chen, Lei Cao, Haorui Shen, Jianyong Li, Wei Wang, Xia Zhao, Kaiyang Ding, Lei Fan
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  • An evaluation of sugemalimab for the treatment of relapsed or refractory extranodal natural killer T-cell lymphoma
    Yingfang Feng, Xia Liu, Jingwei Yu, Zheng Song, Lanfang Li, Lihua Qiu, Shiyong Zhou, Zhengzi Qian, Xianhuo Wang, Huilai Zhang
    Expert Opinion on Biological Therapy.2025; 25(1): 9.     CrossRef
  • Early growth response 1 as a key regulator of PD-L1 expression and immune evasion in extranodal NK/T-cell lymphoma
    Ji Yun Lee, Kui-Jin Kim, Woochan Park, Jeongmin Seo, Minsu Kang, Eun Hee Jung, Sang-A Kim, Koung Jin Suh, Ji-Won Kim, Se Hyun Kim, Jeong-Ok Lee, Jin Won Kim, Yu Jung Kim, Keun-Wook Lee, Jee Hyun Kim, Soo-Mee Bang, Tae Min Kim, Jin Ho Paik
    Blood Cancer Journal.2025;[Epub]     CrossRef
  • Efficacy of combined CD38 and PD-1 inhibition with isatuximab and cemiplimab for relapsed/refractory NK/T-cell lymphoma
    Seok Jin Kim, Jing Quan Lim, Sang Eun Yoon, Deok-Hwan Yang, Ji Hyun Lee, Sung Yong Oh, Yoon Seok Choi, Seong Hyun Jeong, Min Kyoung Kim, Sung Nam Lim, Junhun Cho, Bon Park, Kyung Ju Ryu, Seunghyun Choi, Yoon Park, Kerry May Huifen Lim, Nur Ayuni Binte Muh
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  • Pembrolizumab

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Current Treatment Patterns and the Role of Upfront Autologous Stem Cell Transplantation in Patients with Peripheral T-Cell Lymphoma: A Korean Nationwide, Multicenter Prospective Registry Study (CISL 1404)
Hyungwoo Cho, Dok Hyun Yoon, Dong-Yeop Shin, Youngil Koh, Sung-Soo Yoon, Seok Jin Kim, Young Rok Do, Gyeong-Won Lee, Jae-Yong Kwak, Yong Park, Min Kyoung Kim, Hye Jin Kang, Jun Ho Yi, Kwai Han Yoo, Won Sik Lee, Byeong Bae Park, Jae Cheol Jo, Hyeon-Seok Eom, Hyo Jung Kim, Seong Hyun Jeong, Young-Woong Won, Byeong Seok Sohn, Ji-Hyun Kwon, Cheolwon Suh, Won Seog Kim
Cancer Res Treat. 2023;55(2):684-692.   Published online January 2, 2023
DOI: https://doi.org/10.4143/crt.2022.1434
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
We conducted a nationwide, multicenter, prospective registry study for newly diagnosed patients with peripheral T-cell lymphoma (PTCL) to better define the clinical characteristics, treatment patterns, survival outcomes, and the role of upfront autologous stem cell transplantation (ASCT) in these patients.
Materials and Methods
Patients with PTCL receiving chemotherapy with curative intent were registered and prospectively monitored. All patients were pathologically diagnosed with PTCL.
Results
A total of 191 patients with PTCL were enrolled in this prospective registry study. PTCL, not otherwise specified (PTCL-NOS) was the most common pathologic subtype (n=80, 41.9%), followed by angioimmunoblastic T-cell lymphoma (AITL) (n=60, 31.4%). With a median follow-up duration of 3.9 years, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 39.5% and 60.4%, respectively. The role of upfront ASCT was evaluated in patients who were considered transplant-eligible (n=59). ASCT was performed as an upfront consolidative treatment in 32 (54.2%) of these patients. There were no significant differences in PFS and OS between the ASCT and non-ASCT groups for all patients (n=59) and for patients with PTCL-NOS (n=26). However, in patients with AITL, the ASCT group was associated with significantly better PFS than the non-ASCT group, although there was no significant difference in OS.
Conclusion
The current study demonstrated that the survival outcomes with the current treatment options remain poor for patients with PTCL-NOS. Upfront ASCT may provide a survival benefit for patients with AITL, but not PTCL-NOS.

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  • Epigenetic landscape of angioimmunoblastic T-cell lymphoma: From molecular pathogenesis to precision therapeutics
    Ang Li, Hao Hu, Xuefei Liu, Na Xiao, Feizhen Wu, Miaoxia He
    Genes & Diseases.2026; : 102064.     CrossRef
  • Risk Factors of Disseminated Tumor Cells in the Bone Marrow of Patients With Angioimmunoblastic T‐Cell Lymphoma and Their Impact on Prognosis
    Dongyao Yan, Xueyan Cao, Xiaoqian Wang, Baohong Yue
    International Journal of Laboratory Hematology.2026;[Epub]     CrossRef
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    Yan Feng, Yaxian Ma, Tongjuan Li, Min Liu, Zetong Hong, Qing Yin, Miao Zheng
    Clinical and Experimental Medicine.2025;[Epub]     CrossRef
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    Anu Partanen, Aino Rönkä, Anna Anttalainen, Liisa Ukkola‐Vuoti, Iiro Toppila, Hanne Kuitunen, Tatu Miettinen, Outi Kuittinen
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    Qingyang Zhang, Le Yin, Qinqiao Lai, Yan Zhao, Hongling Peng
    Clinical and Experimental Medicine.2023; 23(8): 4219.     CrossRef
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  • 230 Download
  • 6 Web of Science
  • 8 Crossref
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A New Prognostic Index for Extranodal Natural Killer/T-Cell Lymphoma:Incorporation of Serum β-2 Microglobulin to PINK
Sora Kang, Hyungwoo Cho, Shin Kim, Kyoungmin Lee, Eun Hee Kang, Jung Sun Park, Yoon Sei Lee, Chan-Sik Park, Heounjeong Go, Jooryung Huh, Jin Sook Ryu, Sang-Wook Lee, Seok Jin Kim, Won Seog Kim, Sang Eun Yoon, Young Hyeh Ko, Cheolwon Suh
Cancer Res Treat. 2023;55(1):314-324.   Published online March 31, 2022
DOI: https://doi.org/10.4143/crt.2022.015
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Prognostic Index for Natural Killer Lymphoma (PINK) is the most widely accepted prognostic model for patients withextranodal natural killer/T-cell lymphoma (ENKTL) treated with non-anthracycline–based therapy. We aimed to evaluate the prognostic implications of serum β-2 microglobulin (β2M) in the context of PINK and proposed a new prognostic model.
Materials and Methods
A total of 138 patients who were newly diagnosed with ENKTL and treated with non-anthracycline-based chemotherapy were identified. The cut-off value of high serum β2M was calculated by maximal-chi square methods (4.1 mg/L). A new prognostic model incorporating serum β2M into PINK was proposed and validated in an independent validation cohort (n=88).
Results
The patients’ median age was 53.5 years (range, 19 to 80 years). Patients with high serum β2M levels had significantly worse overall survival (OS) and progression-free survival (PFS). In multivariate analysis, high serum β2M was an independent adverse prognostic factor for OS. A new PINK-B (Prognostic Index for Natural Killer Lymphoma-serum β-2 microglobulin) model stratifiedpatients into three groups with distinct OS and PFS in the training cohort (3-year OS, 84.1% [95% confidence interval, 75.1 to 94.2], 46.8% [36.1 to 60.8] and 17.6% [6.3 to 49.2] for the low-, intermediate, and high-risk groups, respectively; 3-year PFS, 70.6% [59.4 to 83.8], 35.9% [25.9 to 49.8], and 7.35% [1.1 to 46.7] for the low-, intermediate-, and high-risk groups, respectively). The PINK-B model was further validated in an independent cohort.
Conclusion
Serum β2M is an independent prognostic factor for ENKTL patients. The new serum β2M-based prognostic model may be useful for identifying ultra-high-risk patients, and it can easily be adopted into daily clinical practice.

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Hematologic Malignancy
Prognostic Stratification of Patients with Burkitt Lymphoma Using Serum β2-microglobulin Levels
Hyung-Don Kim, Hyungwoo Cho, Shin Kim, Kyoungmin Lee, Eun Hee Kang, Jung Sun Park, Chan-Sik Park, Jooryung Huh, Jin Sook Ryu, Sang-Wook Lee, Dok-Hyun Yoon, Seok Jin Kim, Young Hyeh Ko, Won Seog Kim, Cheolwon Suh
Cancer Res Treat. 2021;53(3):847-856.   Published online December 17, 2020
DOI: https://doi.org/10.4143/crt.2020.1060
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
We aimed to investigate the prognostic value of serum β2-microglobulin for patients with Burkitt lymphoma (BL) and to propose a risk-stratifying classification system.
Materials and Methods
A prospective registry-based cohort study of BL patients treated with dose-intensive or effective dose-adjusted chemotherapies (n=81) was conducted. Survival outcomes were compared based on previously reported risk groups and/or serum β2-microglobulin levels. A risk-stratifying classification system incorporating serum β2-microglobulin levels was proposed and validated in an independent validation cohort (n=60).
Results
The median age was 47 years, and 57 patients (70.4%) were male. Patients with high serum β2-microglobulin levels (> 2 mg/L) had significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.01 for both). Serum β2-microglobulin levels further stratified patients in the low-risk and high-risk groups in terms of PFS (p=0.010 and p=0.044, respectively) and OS (p=0.014 and p=0.026, respectively). Multivariate analyses revealed that a high serum β2-microglobulin level (> 2 mg/L) was independently associated with a shorter PFS (hazards ratio [HR], 3.56; p=0.047) and OS (HR, 4.66; p=0.043). The new classification system incorporating the serum β2-microglobulin level allowed the stratification of patients into three distinct risk subgroups with 5-year OS rates of 100%, 89.5%, and 62.5%. In an independent cohort of BL, the system was validated by stratifying patients with different survival outcomes.
Conclusion
Serum β2-microglobulin level is an independent prognostic factor for BL patients. The proposed β2-microglobulin–based classification system could stratify patients with distinct survival outcomes, which may help define appropriate treatment approaches for individual patients.

Citations

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    Yajiao Liu, Li Sheng, Haiying Hua, Jingfen Zhou, Ying Zhao, Bei Wang
    Technology in Cancer Research & Treatment.2023;[Epub]     CrossRef
  • Prognostic significance of serum β2-microglobulin levels in patients with peripheral T-cell lymphoma not otherwise specified
    Hyung-Don Kim, Hyungwoo Cho, Byeong Seok Sohn, Chan-Sik Park, Jooryung Huh, Jin Sook Ryu, Sang-Wook Lee, Sang Eun Yoon, Seok Jin Kim, Young Hyeh Ko, Won Seog Kim, Cheolwon Suh
    Leukemia & Lymphoma.2022; 63(1): 124.     CrossRef
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