Journal of Pathology and Translational Medicine

Original Articles

The combination of CDX2 expression status and tumor-infiltrating lymphocyte density as a prognostic factor in adjuvant FOLFOX-treated patients with stage III colorectal cancers: Ji-Ae Lee, Hye Eun Park, Hye-Yeong Jin, Lingyan Jin, Seung Yeon Yoo, Nam-Yun Cho, Jeong Mo Bae, Jung Ho Kim, Gyeong Hoon Kang; Received June 3, 2024 Accepted September 26, 2024 Published online October 24, 2024; DOI: https://doi.org/10.4132/jptm.2024.09.26 [Epub ahead of print]

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Abstract PDF Supplementary Material: Background
Colorectal carcinomas (CRCs) with caudal-type homeobox 2 (CDX2) loss are recognized to pursue an aggressive behavior but tend to be accompanied by a high density of tumor-infiltrating lymphocytes (TILs). However, little is known about whether there is an interplay between CDX2 loss and TIL density in the survival of patients with CRC.
Methods
Stage III CRC tissues were assessed for CDX2 loss using immunohistochemistry and analyzed for their densities of CD8 TILs in both intraepithelial (iTILs) and stromal areas using a machine learning-based analytic method.
Results
CDX2 loss was significantly associated with a higher density of CD8 TILs in both intraepithelial and stromal areas. Both CDX2 loss and a high CD8 iTIL density were found to be prognostic parameters and showed hazard ratios of 2.314 (1.050–5.100) and 0.378 (0.175–0.817), respectively, for cancer-specific survival. A subset of CRCs with retained CDX2 expression and a high density of CD8 iTILs showed the best clinical outcome (hazard ratio of 0.138 [0.023–0.826]), whereas a subset with CDX2 loss and a high density of CD8 iTILs exhibited the worst clinical outcome (15.781 [3.939–63.230]).
Conclusions
Altogether, a high density of CD8 iTILs did not make a difference in the survival of patients with CRC with CDX2 loss. The combination of CDX2 expression and intraepithelial CD8 TIL density was an independent prognostic marker in adjuvant chemotherapy-treated patients with stage III CRC.

Tumor-infiltrating T lymphocytes evaluated using digital image analysis predict the prognosis of patients with diffuse large B-cell lymphoma: Yunjoo Cho, Jiyeon Lee, Bogyeong Han, Sang Eun Yoon, Seok Jin Kim, Won Seog Kim, Junhun Cho; J Pathol Transl Med. 2024;58(1):12-21. Published online January 10, 2024; DOI: https://doi.org/10.4132/jptm.2023.11.02

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Abstract PDF: Background
The implication of the presence of tumor-infiltrating T lymphocytes (TIL-T) in diffuse large B-cell lymphoma (DLBCL) is yet to be elucidated. We aimed to investigate the effect of TIL-T levels on the prognosis of patients with DLBCL.
Methods
Ninety-six patients with DLBCL were enrolled in the study. The TIL-T ratio was measured using QuPath, a digital pathology software package. The TIL-T ratio was investigated in three foci (highest, intermediate, and lowest) for each case, resulting in TIL-T–Max, TIL-T–Intermediate, and TIL-T–Min. The relationship between the TIL-T ratios and prognosis was investigated.
Results
When 19% was used as the cutoff value for TIL-T–Max, 72 (75.0%) and 24 (25.0%) patients had high and low TIL-T–Max, respectively. A high TIL-T–Max was significantly associated with lower serum lactate dehydrogenase levels (p < .001), with patient group who achieved complete remission after RCHOP therapy (p < .001), and a low-risk revised International Prognostic Index score (p < .001). Univariate analysis showed that patients with a low TIL-T–Max had a significantly worse prognosis in overall survival compared to those with a high TIL-T–Max (p < .001); this difference remained significant in a multivariate analysis with Cox proportional hazards (hazard ratio, 7.55; 95% confidence interval, 2.54 to 22.42; p < .001).
Conclusions
Patients with DLBCL with a high TIL-T–Max showed significantly better prognosis than those with a low TIL-T–Max, and the TIL-T–Max was an independent indicator of overall survival. These results suggest that evaluating TIL-T ratios using a digital pathology system is useful in predicting the prognosis of patients with DLBCL.

Immunohistochemical expression of programmed death-ligand 1 and CD8 in glioblastomas: Dina Mohamed El Samman, Manal Mohamed El Mahdy, Hala Sobhy Cousha, Zeinab Abd El Rahman Kamar, Khaled Abdel Karim Mohamed, Hoda Hassan Abou Gabal; J Pathol Transl Med. 2021;55(6):388-397. Published online October 14, 2021; DOI: https://doi.org/10.4132/jptm.2021.08.04

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Abstract PDF

Background
Glioblastoma is the most aggressive primary malignant brain tumor in adults and is characterized by poor prognosis. Immune evasion occurs via programmed death-ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) interaction. Some malignant tumors have responded to PD-L1/PD-1 blockade treatment strategies, and PD-L1 has been described as a potential predictive biomarker. This study discussed the expression of PD-L1 and CD8 in glioblastomas.
Methods
Thirty cases of glioblastoma were stained immunohistochemically for PD-L1 and CD8, where PD-L1 expression in glioblastoma tumor tissue above 1% is considered positive and CD-8 is expressed in tumor infiltrating lymphocytes. The expression of each marker was correlated with clinicopathologic parameters. Survival analysis was conducted to correlate progression-free survival (PFS) and overall survival (OS) with PD-L1 and CD8 expression.
Results
Diffuse/fibrillary PD-L1 was expressed in all cases (mean expression, 57.6%), whereas membranous PD-L1 was expressed in six of 30 cases. CD8-positive tumor-infiltrating lymphocytes (CD8⁺ TILs) had a median expression of 10%. PD-L1 and CD8 were positively correlated (p = .001). High PD-L1 expression was associated with worse PFS and OS (p = .026 and p = .001, respectively). Correlation of CD8⁺ TILs percentage with age, sex, tumor site, laterality, and outcomes were statistically insignificant. Multivariate analysis revealed that PD-L1 was the only independent factor that affected prognosis.
Conclusions
PD-L1 expression in patients with glioblastoma is robust; higher PD-L1 expression is associated with lower CD8+ TIL expression and worse prognosis.

Citations

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Tumor-associated microenvironment, PD-L1 expression and their relationship with immunotherapy in glioblastoma, IDH-wild type: A comprehensive review with emphasis on the implications for neuropathologists
Giuseppe Broggi, Giuseppe Angelico, Jessica Farina, Giordana Tinnirello, Valeria Barresi, Magda Zanelli, Andrea Palicelli, Francesco Certo, Giuseppe Barbagallo, Gaetano Magro, Rosario Caltabiano
Pathology - Research and Practice.2024; 254: 155144. CrossRef
Analysis of PD-L1 and CD3 Expression in Glioblastoma Patients and Correlation with Outcome: A Single Center Report
Navid Sobhani, Victoria Bouchè, Giovanni Aldegheri, Andrea Rocca, Alberto D’Angelo, Fabiola Giudici, Cristina Bottin, Carmine Antonio Donofrio, Maurizio Pinamonti, Benvenuto Ferrari, Stefano Panni, Marika Cominetti, Jahard Aliaga, Marco Ungari, Antonio Fi
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Immuno-PET Imaging of Tumour PD-L1 Expression in Glioblastoma
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Programmed death-ligand 1 expression and tumor-infiltrating lymphocytes in non-small cell lung cancer: association with clinicopathologic parameters: Gaurav Garg, Kuruswamy Thurai Prasad, Navneet Singh, Parul Gupta, Valliappan Muthu, Ashim Das, Amanjit Bal; J Pathol Transl Med. 2021;55(6):398-405. Published online October 6, 2021; DOI: https://doi.org/10.4132/jptm.2021.08.08

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Abstract PDF Supplementary Material

Background
Data on the prevalence of programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in non–small cell lung cancer (NSCLC) and their clinical significance in Indian patients are limited.
Methods
Newly diagnosed NSCLC cases (adenocarcinoma or squamous cell carcinoma [SqCC] histology) were included in the present study. The TILs were evaluated based on morphology on hematoxylin and eosin–stained slides. PD-L1 expression in tumors was assessed using immunohistochemistry with rabbit monoclonal antibody (SP263) on the Ventana automated immunostainer. Tumors with PD-L1 expression > 50% on tumor cells were considered PD-L1–positive. Tumors in which TILs occupy > 25% of stroma were considered to have high TILs. The association of PD-L1 expression and TILs with various clinical parameters including overall survival (OS) was investigated.
Results
The present study included 128 cases of NSCLC (67 adenocarcinoma, 61 SqCC). PD-L1 positivity was observed in 17.2% of the patients with NSCLC. Baseline characteristics of PD-L1–positive subjects were similar to PD-L1–negative subjects except for a higher prevalence of liver metastasis (18.2% vs. 2.8%; p = .018) and a higher probability of diagnosis from extrapulmonary biopsies. High TILs were observed in 26.6% of the subjects. However, PD-L1 expression and high TIL did not affect OS.
Conclusions
PD-L1 positivity and high TILs were observed in 20% and 25% of the patients with NSCLC, respectively, however, neither were predictors of survival in SqCC.

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Multiplex plasma protein assays as a diagnostic tool for lung cancer
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Review

Tumor immune response and immunotherapy in gastric cancer: Yoonjin Kwak, An Na Seo, Hee Eun Lee, Hye Seung Lee; J Pathol Transl Med. 2020;54(1):20-33. Published online November 1, 2019; DOI: https://doi.org/10.4132/jptm.2019.10.08

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Abstract PDF

Remarkable developments in immuno-oncology have changed the landscape of gastric cancer (GC) treatment. Because immunotherapy intervenes with tumor immune response rather than directly targeting tumor cells, it is important to develop a greater understanding of tumor immunity. This review paper summarizes the tumor immune reaction and immune escape mechanisms while focusing on the role of T cells and their co-inhibitory signals, such as the immune checkpoint molecules programmed death-1 and programmed deathligand 1 (PD-L1). This paper also describes past clinical trials of immunotherapy for patients with GC and details their clinical implications. Strong predictive markers are essential to improve response to immunotherapy. Microsatellite instability, Epstein-Barr virus, PD-L1 expression, and tumor mutational burden are now regarded as potent predictive markers for immunotherapy in patients with GC. Novel immunotherapy and combination therapy targeting new immune checkpoint molecules such as lymphocyte-activation gene 3, T cell immunoglobulin, and mucin domain containing-3, and indoleamine 2,3-dioxygenase have been suggested, and trials are ongoing to evaluate their safety and efficacy. Immunotherapy is an important treatment option for patients with GC and has great potential for improving patient outcome, and further research in immuno-oncology should be carried out.

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Original Articles

Association between p53 Expression and Amount of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Miseon Lee, In Ah Park, Sun-Hee Heo, Young-Ae Kim, Gyungyub Gong, Hee Jin Lee; J Pathol Transl Med. 2019;53(3):180-187. Published online March 11, 2019; DOI: https://doi.org/10.4132/jptm.2019.02.08

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Abstract PDF

Background
Most triple-negative breast cancers (TNBCs) have a high histologic grade, are associated with high endoplasmic stress, and possess a high frequency of TP53 mutations. TP53 missense mutations lead to the production of mutant p53 protein and usually show high levels of p53 protein expression. Tumor-infiltrating lymphocytes (TILs) accumulate as part of the anti-tumor immune response and have a strong prognostic and predictive significance in TNBC. We aimed to elucidate the association between p53 expression and the amount of TILs in TNBC.
Methods
In 678 TNBC patients, we evaluated TIL levels and expression of endoplasmic stress molecules. Immunohistochemical examination of p53 protein expression was categorized into three groups: no, low, and high expression.
Results
No, low, and high p53 expression was identified in 44.1% (n = 299), 20.1% (n = 136), and 35.8% (n = 243) of patients, respectively. Patients with high p53 expression showed high histologic grade (p < .001), high TIL levels (p = .009), and high expression of endoplasmic reticulum stress-associated molecules (p-eIF2a, p = .013; XBP1, p = .007), compared to patients with low p53 expression. There was no significant difference in disease-free (p = .406) or overall survival rates (p = .444) among the three p53 expression groups.
Conclusions
High p53 expression is associated with increased expression of endoplasmic reticulum stress molecules and TIL influx.

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Loss of Human Leukocyte Antigen Class I Expression Is Associated with Poor Prognosis in Patients with Advanced Breast Cancer: Hong Sik Park, Uiju Cho, So Young Im, Chang Young Yoo, Ji Han Jung, Young Jin Suh, Hyun Joo Choi; J Pathol Transl Med. 2019;53(2):75-85. Published online November 14, 2018; DOI: https://doi.org/10.4132/jptm.2018.10.11

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Abstract PDF

Background
Human leukocyte antigen class I (HLA-I) molecules play important roles in regulating immune responses. Loss or reduction of HLA-I expression has been shown to be associated with prognosis in several cancers. Regulatory T-cells (Tregs) also play critical functions in immune response regulation. Evaluation of HLA-I expression status by the EMR8-5 antibody and its clinical impact in breast cancer have not been well studied, and its relationship with Tregs remains unclear.
Methods
We evaluated HLA-I expression and Treg infiltration by immunohistochemistry in 465 surgically resected breast cancer samples. We examined the correlation between HLA-I expression and Treg infiltration and clinicopathologic characteristics and survival analyses were performed.
Results
Total loss of HLA-I expression was found in 84 breast cancer samples (18.1%). Univariate survival analysis revealed that loss of HLA-I expression was significantly associated with worse disease-specific survival (DSS) (p = .029). HLA-I was not an independent prognostic factor in the entire patient group, but it was an adverse independent prognostic factor for DSS in patients with advanced disease (stage II–IV) (p = .031). Treg numbers were significantly higher in the intratumoral stroma of HLA-I–positive tumors than in HLA-I–negative tumors (median 6.3 cells/high power field vs 2.1 cells/high power field, p < .001). However, Tregs were not an independent prognostic factor in our cohort.
Conclusions
Our findings suggest that the loss of HLA-I expression is associated with poor prognosis in breast cancer patients, highlighting the role of HLA-I alterations in immune evasion mechanisms of breast cancer. HLA-I could be a promising marker that enables the application of more effective and precise immunotherapies for patients with advanced breast cancer.

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Do Helper T Cell Subtypes in Lymphocytic Thyroiditis Play a Role in the Antitumor Effect?: Seok Woo Yang, Seong-Ho Kang, Kyung Rae Kim, In Hong Choi, Hang Seok Chang, Young Lyun Oh, Soon Won Hong; J Pathol Transl Med. 2016;50(5):377-384. Published online September 15, 2016; DOI: https://doi.org/10.4132/jptm.2016.07.25

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Abstract PDF

Background
Papillary thyroid carcinoma (PTC) is frequently accompanied by lymphocytic thyroiditis (LT). Some reports claim that Hashimoto’s thyroiditis (the clinical form of LT) enhances the likelihood of PTC; however, others suggest that LT has antitumor activity. This study was aimed to find out the relationship between the patterns of helper T cell (Th) cytokines in thyroid tissue of PTC with or without LT and the clinicopathological manifestation of PTC.
Methods
Fresh surgical samples of PTC with (13 cases) or without (10 cases) LT were used. The prognostic parameters (tumor size, extra-thyroidal extension of PTC, and lymph node metastasis) were analyzed. The mRNA levels of two subtypes of Th cytokines, Th1 (tumor necrosis factor α [TNF-α], interferon γ [IFN-γ ], and interleukin [IL] 2) and Th2 (IL-4 and IL-10), were analyzed. Because most PTC cases were microcarcinomas and recent cases without clinical follow-up, negative or faint p27 immunoreactivity was used as a surrogate marker for lymph node metastasis.
Results
PTC with LT cases showed significantly higher expression of TNF-α (p = .043), IFN-γ (p < .010), IL-4 (p = .015) than those without LT cases. Although the data were not statistically significant, all analyzed cytokines (except for IL-4) were highly expressed in the cases with higher expression of p27 surrogate marker.
Conclusions
These results indicate that mixed Th1 (TNF-α, IFN-γ , and IL-2) and Th2 (IL-10) immunity might play a role in the antitumor effect in terms of lymph node metastasis.

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Review

Current Issues and Clinical Evidence in Tumor-Infiltrating Lymphocytes in Breast Cancer: Sung Gwe Ahn, Joon Jeong, SoonWon Hong, Woo Hee Jung; J Pathol Transl Med. 2015;49(5):355-363. Published online August 17, 2015; DOI: https://doi.org/10.4132/jptm.2015.07.29

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239 Download
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Abstract PDF

With the advance in personalized therapeutic strategies in patients with breast cancer, there is an increasing need for biomarker-guided therapy. Although the immunogenicity of breast cancer has not been strongly considered in research or practice, tumor-infiltrating lymphocytes (TILs) are emerging as biomarkers mediating tumor response to treatments. Earlier studies have provided evidence that the level of TILs has prognostic value and the potential for predictive value, particularly in triple-negative and human epidermal growth factor receptor 2–positive breast cancer. Moreover, the level of TILs has been associated with treatment outcome in patients undergoing neoadjuvant chemotherapy. To date, no standardized methodology for measuring TILs has been established. In this article, we review current issues and clinical evidence for the use of TILs in breast cancer.

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Cytoplasmic expression of high mobility group B1 (HMGB1) is associated with tumor‐infiltrating lymphocytes (TILs) in breast cancer
Hee Jin Lee, Ahrong Kim, In Hye Song, In Ah Park, Jong Han Yu, Jin Hee Ahn, Gyungyub Gong
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Clinical pharmacologic aspects of immune checkpoint inhibitors in cancer therapy
Kyu-pyo Kim, Hun Jung
Translational and Clinical Pharmacology.2016; 24(1): 7. CrossRef
The next level of 3D tumour models: immunocompetence
Agata Nyga, Joana Neves, Katerina Stamati, Marilena Loizidou, Mark Emberton, Umber Cheema
Drug Discovery Today.2016; 21(9): 1421. CrossRef
An Examination of the Local Cellular Immune Response to Examples of Both Ductal Carcinoma In Situ (DCIS) of the Breast and DCIS With Microinvasion, With Emphasis on Tertiary Lymphoid Structures and Tumor Infiltrating Lymphoctytes
Ahrong Kim, Sun-Hee Heo, Young-Ae Kim, Gyungyub Gong, Hee Jin Lee
American Journal of Clinical Pathology.2016; 146(1): 137. CrossRef
High Ki67/BCL2 index is associated with worse outcome in early stage breast cancer
Kyueng-Whan Min, Dong-Hoon Kim, Sung-Im Do, Jung-Soo Pyo, Seoung Wan Chae, Jin Hee Sohn, Kyungeun Kim, Hyun Joo Lee, Dong Hyun Kim, Sukjoong Oh, Seon Hyeong Choi, Yong Lai Park, Chan Heun Park, Mi Jung Kwon, Kyoung Min Moon
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Original Articles

Prognostic Significance of Absolute Lymphocyte Count/Absolute Monocyte Count Ratio at Diagnosis in Patients with Multiple Myeloma: Su-Jin Shin, Jin Roh, Misung Kim, Min Jung Jung, Young Wha Koh, Chan-Sik Park, Dok Hyun Yoon, Cheolwon Suh, Chan-Jeong Park, Hyun Sook Chi, Jooryung Huh; Korean J Pathol. 2013;47(6):526-533. Published online December 24, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.6.526

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Abstract PDF

Background

Absolute lymphocyte count (ALC) in peripheral blood has recently been reported to be an independent prognostic factor in multiple myeloma (MM). Previous studies indicated that the absolute monocyte count (AMC) in peripheral blood reflects the state of the tumor microenvironment in lymphomas. Neither the utility of the AMC nor its relationship with ALC has been studied in MM.

Methods

The prognostic value of ALC, AMC, and the ALC/AMC ratio at the time of diagnosis was retrospectively examined in 189 patients with MM.

Results

On univariate analysis, low ALC (<1,400 cells/µL), high AMC (≥490 cells/µL), and low ALC/AMC ratio (<2.9) were correlated with worse overall survival (OS) (p=.002, p=.038, and p=.001, respectively). On multivariate analysis, the ALC/AMC ratio was an independent prognostic factor (p=.047), whereas ALC and AMC were no longer statistical significant. Low ALC, high AMC, and low ALC/AMC ratio were associated with poor prognostic factors such as high International Staging System stage, plasmablastic morphology, hypoalbuminemia, and high β2-microglobulin.

Conclusions

Univariate analysis demonstrated that changes in ALC, AMC, and the ALC/AMC ratio are associated with patient survival in MM. Multivariate analysis showed that, of these factors, the ALC/AMC ratio was an independent prognostic factor for OS.

Citations

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Descriptive analysis and prognostic factors in cats with myeloma‐related disorders: A multicenter retrospective study of 50 cases
Lorris Lecot, Isabelle Desmas‐Bazelle, Sarah Benjamin, Pauline De Fornel, Frédérique Ponce, Matthew Kornya, Loïc Desquilbet, Claire Beaudu‐Lange, Catherine Ibisch, David Sayag, Ghita Benchekroun, Jérémy Béguin
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Definers and drivers of functional high-risk multiple myeloma: insights from genomic, transcriptomic, and immune profiling
Rahul Banerjee, Kara I. Cicero, Sarah S. Lee, Andrew J. Cowan
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Normal Absolute Monocyte Count in Combination with Normal/High Absolute Lymphocyte Count at the Time of Relapse is Associated with Improved Survival in Patients with Early Relapsed Acute Myeloid Leukemia
Yu Zhang, Kanchun Dai, Qianying Zhang, Yisha Huang, Yiyun Feng, Deeksha Bhardwaj, Kang Yu, Jianhua Feng
Cancer Investigation.2021; 39(6-7): 550. CrossRef
Real World Experience of Daratumumab: Evaluating Lymphopenia and Adverse Events in Multiple Myeloma Patients
Francesca Cottini, Ying Huang, Nita Williams, Naresh Bumma, Abdullah M. Khan, Maria Chaudhry, Srinivas Devarakonda, Yvonne A. Efebera, Don M. Benson, Ashley E. Rosko
Frontiers in Oncology.2021;[Epub] CrossRef
Are the Derived Indexes of Peripheral Whole Blood Cell Counts (NLR, PLR, LMR/MLR) Clinically Significant Prognostic Biomarkers in Multiple Myeloma? A Systematic Review And Meta-Analysis
Xinwen Zhang, Jialin Duan, Zhenyu Wen, Hao Xiong, Xiaomin Chen, Yang Liu, Kunyu Liao, Chunlan Huang
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Combined immune score of lymphocyte to monocyte ratio and immunoglobulin levels predicts treatment-free survival of multiple myeloma patients after autologous stem cell transplant
Karen Sweiss, Jonathan Lee, Nadim Mahmud, Gregory S. Calip, Youngmin Park, Dolores Mahmud, Damiano Rondelli, Pritesh R. Patel
Bone Marrow Transplantation.2020; 55(1): 199. CrossRef
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Yan Gu, Yuanyuan Jin, Jie Ding, Wu Yujie, Qinglin Shi, Xiaoyan Qu, Sishu Zhao, Jianyong Li, Chen Lijuan
Leukemia & Lymphoma.2020; 61(8): 1869. CrossRef
Normal Absolute Monocyte Count at the Time of Relapse is Associated with Improved Survival After First Salvage Therapy in Adult Patients with Early Relapsed B-Lineage Acute Lymphoblastic Leukemia

Yi-fen Shi, Na Wang, Zi-yang Huang, Rong-rong Chen, Yi-sha Huang, Yi-yi Zhu, Chong-yun Xing, Bin Liang, Kang Yu, Jian-hua Feng
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Peripheral blood biomarkers of early immune reconstitution in newly diagnosed multiple myeloma
Moritz Binder, S. Vincent Rajkumar, Martha Q. Lacy, Morie A. Gertz, Francis K. Buadi, Angela Dispenzieri, Yi L. Hwa, Amie Fonder, Miriam Hobbs, Suzanne R. Hayman, Steven R. Zeldenrust, John A. Lust, Stephen J. Russell, Nelson Leung, Prashant Kapoor, Ronal
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Liyuan Tang, Na Wang, Chongyun Xing, Qiang Zhuang, Bin Liang, Lan Sun, Yi Chen, Yan Qian, Zhijian Shen, Songfu Jiang, Kang Yu, Jianhua Feng
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A lower ALC/AMC ratio is associated with poor prognosis of peripheral T-cell lymphoma-not otherwise specified
Qian Li, Shuang Gao, Jing Ma, Su Liu, Yuanfang Yue, Lin Chen, Han Li, Xue Wang, Dongying Li, Zeng Cao, Zhigang Zhao, Xiaofang Wang, Yong Yu, Yizhuo Zhang, Yafei Wang
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Peripheral Blood Lymphocyte-to-Monocyte Ratio as a Useful Prognostic Factor in Newly Diagnosed Multiple Myeloma
Ying Tian, Yue Zhang, Wan-Qiu Zhu, Xiao-Lei Chen, He-Bing Zhou, Wen-Ming Chen
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Significance of the absolute lymphocyte/monocyte ratio as a prognostic immune biomarker in newly diagnosed multiple myeloma
T Dosani, F Covut, R Beck, J J Driscoll, M de Lima, E Malek
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Lymphocyte-to-monocyte ratio can predict mortality in pancreatic adenocarcinoma
Gurshawn Singh, Ammar Nassri, David Kim, Hong Zhu, Zeeshan Ramzan
World Journal of Gastrointestinal Pharmacology and Therapeutics.2017; 8(1): 60. CrossRef
Bone marrow microenvironmental CD4 + and CD8 + lymphocyte infiltration patterns define overall- and progression free survival in standard risk multiple myeloma – an analysis from the Austrian Myeloma Registry
Wolfgang Willenbacher, Ella Willenbacher, Claudia Zelle-Rieser, Rainer Biedermann, Roman Weger, Karin Jöhrer, Andrea Brunner
Leukemia & Lymphoma.2016; 57(6): 1478. CrossRef
Absolute lymphocyte count as a prognostic marker in newly diagnosed multiple myeloma patients
C. Suriu, L. Akria, D. Azoulay, E. Shaoul, M. Barhoum, A. Braester
International Journal of Laboratory Hematology.2016;[Epub] CrossRef
The Peripheral Blood Mononuclear Cell Count Is Associated With Bone Health in Elderly Men
Xianfeng Lin, Hejun Yu, Chenchen Zhao, Yu Qian, Dun Hong, Kangmao Huang, Jian Mo, An Qin, Xiangqian Fang, Shunwu Fan
Medicine.2016; 95(15): e3357. CrossRef
Prognostic role of lymphocyte to monocyte ratio for patients with cancer: evidence from a systematic review and meta-analysis
Liangyou Gu, Hongzhao Li, Luyao Chen, Xin Ma, Xintao Li, Yu Gao, Yu Zhang, Yongpeng Xie, Xu Zhang
Oncotarget.2016; 7(22): 31926. CrossRef
Do lymphocytes count in myeloma? Are we absolutely sure?
Tamar Tadmor
Leukemia & Lymphoma.2015; 56(5): 1193. CrossRef
Absolute lymphocyte count is unrelated to overall survival in newly diagnosed elderly patients with multiple myeloma treated with immunomodulatory drugs
Mariasanta Napolitano, Giorgia Saccullo, Roberto Bono, Antonio Branca, Clotilde Cangialosi, Salvatrice Mancuso, Simona Raso, Gerlando Quintini, Maria Grazia Lipari, Francesco Fabbiano, Giorgina Specchia, Alberto Dolce, Francesco Di Raimondo, Sergio Siragu
Leukemia & Lymphoma.2015; 56(5): 1507. CrossRef
Distinct Transcriptional and Anti-Mycobacterial Profiles of Peripheral Blood Monocytes Dependent on the Ratio of Monocytes: Lymphocytes
Vivek Naranbhai, Helen A. Fletcher, Rachel Tanner, Matthew K. O'Shea, Helen McShane, Benjamin P. Fairfax, Julian C. Knight, Adrian V.S. Hill
EBioMedicine.2015; 2(11): 1619. CrossRef
Prognostic value of absolute monocyte count in chronic lymphocytic leukaemia
László Szerafin, János Jakó, Ferenc Riskó
Orvosi Hetilap.2015; 156(15): 592. CrossRef
The lymphocyte to monocyte ratio in peripheral blood represents a novel prognostic marker in patients with pancreatic cancer
Michael Stotz, Joanna Szkandera, Tatjana Stojakovic, Julia Seidel, Hellmut Samonigg, Peter Kornprat, Renate Schaberl-Moser, Fridericke Seggewies, Gerald Hoefler, Armin Gerger, Martin Pichler
Clinical Chemistry and Laboratory Medicine (CCLM).2015;[Epub] CrossRef

Progressive Increase of Regulatory T Cells and Decrease of CD8+ T Cells and CD8+ T Cells/Regulatory T Cells Ratio during Colorectal Cancer Development: Tae Jung Jang; Korean J Pathol. 2013;47(5):443-451. Published online October 25, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.5.443

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Abstract PDF

Background

We examined the distribution of CD8+ T cells and regulatory T cells (Tregs), measured the CD8+ T cell/Tregs ratio, investigated the relationship between Tregs and cyclooxygenase-2 (COX-2) expression during colorectal cancer (CRC) development.

Methods

We performed immunohistochemical staining for CD8, forkhead box P3, E-cadherin, and COX-2 in 32 cases of invasive CRC, 10 cases of intramucosal CRC, 27 cases of high-grade tubular adenoma, 22 cases of low-grade tubular adenoma, and 32 cases of non-neoplastic conditions.

Results

We observed a progressive increase in Tregs, and a decrease in CD8+ T cells and the CD8+ T cells/Tregs ratio during CRC development. The alterations were most severe in high-grade tubular adenoma and CRC. COX-2 expression was positively associated with Tregs infiltration. The degree of T cell infiltration differed among tumor compartment and the ratio in the tumor center was the lowest of all areas. The ratio and number of CD8+ T cells in the tumor center and the invasive front of invasive CRC were associated with gender, differentiation, node metastasis and tumor budding.

Conclusions

Alteration in the distribution of both CD8+T cells and Tregs may contribute to the generation of an immune environment suitable for the development and progression of CRC.

Citations

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Molecular mechanisms of tumour budding and its association with microenvironment in colorectal cancer
Phimmada Hatthakarnkul, Jean A. Quinn, Aula Ammar, Gerard Lynch, Hester Van Wyk, Donald C. McMillan, Chanitra Thuwajit, Joanne Edwards
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Significance of Foxp3 Positive Regulatory T Cell and Tumor Infiltrating T Lymphocyte in Triple Negative Breast Cancer.: Hanna Kang, Harin Cheong, Min Sun Cho, Heasoo Koo, Woon Sup Han, Kyung Eun Lee, Byung In Moon, Sun Hee Sung; Korean J Pathol. 2011;45(1):53-61.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.1.53

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Abstract PDF

BACKGROUND
Triple negative breast cancer (TNBC) is defined as a lack of the expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 in breast cancer. Many TNBCs show a profound infiltration of tumor infiltrating lymphocytes (TILs). It is still uncertain whether these TILs are protumoral or antitumoral. Regulatory T cells (Tregs) play a role in inducing immune tolerance to antigens, and they may be selectively recruited by cancer cells. This study was conducted to evaluate the significance of TILs with an emphasis on forkhead box p3 (Foxp3), which is a marker for CD25+CD4+ Treg in TNBC.
METHODS
We investigated the Foxp3, CD8 and CD4 expressions in 100 cases of TNBC by immunohistochemistry and using a tissue microarray. The Foxp3 expression was divided as the high and low infiltration groups (cut-off value=20).
RESULTS
The high infiltration group was correlated with higher histologic and nuclear grades. However, Foxp3+ Tregs were decreased in the T3 and T4 TNBCs as compared to that of the T1 and T2 TNBCs. No significant differences were found for the nodal status, lymphovascular invasion, stage, recurrence and overall survival.
CONCLUSIONS
High Foxp3+ Treg infiltration in TNBC is correlated with the nuclear and histologic grades, but there was no relation to recurrence and overall survival.

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Predictive Value of Tertiary Lymphoid Structures Assessed by High Endothelial Venule Counts in the Neoadjuvant Setting of Triple-Negative Breast Cancer
In Hye Song, Sun-Hee Heo, Won Seon Bang, Hye Seon Park, In Ah Park, Young-Ae Kim, Suk Young Park, Jin Roh, Gyungyub Gong, Hee Jin Lee
Cancer Research and Treatment.2017; 49(2): 399. CrossRef
Zonal Difference and Prognostic Significance of Foxp3 Regulatory T Cell Infiltration in Breast Cancer
Sewha Kim, Anbok Lee, Woosung Lim, Sanghui Park, Min Sun Cho, Heasoo Koo, Byung-In Moon, Sun Hee Sung
Journal of Breast Cancer.2014; 17(1): 8. CrossRef

Distribution of Dendritic Cells and Regulatory T-Cells in Cutaneous Lymphomas.: Changyoung Yoo, Young Seon Hong, Baik Kee Cho, Sang Ho Kim, Sang In Shim, Chang Suk Kang; Korean J Pathol. 2010;44(6):581-588.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.6.581

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Abstract PDF: BACKGROUND
Dendritic cells (DCs) play an important role in immune reactions. This study was designed to identify the distribution patterns of DCs and regulatory T-cells (Tregs) in cutaneous lymphomas.
METHODS
Immunohistochemistry was used to determine langerin expression on Langerhans cells, CD11b on inflammatory DCs, CD209 and CD11c on dermal DCs, CD303 on plasmacytic DCs, and Foxp3 on Tregs in 81 cases of cutaneous lymphomas.
RESULTS
Various DCs and Tregs were identified in most cutaneous lymphomas. Plasmacytic DCs, inflammatory DCs and Tregs were identified mainly in tumor areas, whereas dermal DCs were distributed both in the tumor and stromal areas. Among DCs, dermal DCs were most prominently identified in the cutaneous lymphomas not only in the tumor area but also in the stroma. The intense stromal infiltration of dermal DCs was consistent finding in T-cell lymphomas. Diffuse large B-cell lymphoma (DLBCL), not otherwise specified also showed intense stromal infiltration of dermal DCs, but stromal infiltration in DLBCL, leg type was relatively scant.
CONCLUSIONS
The results suggest that all types of DCs and Tregs are involved in cutaneous lymphoma tumor immunity. Among them dermal DCs may play a dominant role.

Frequency of Intrahepatic FoxP3+ Regulatory T cells during the Natural Course of Chronic Hepatitis B: An Immunohistochemical Study Using Needle-Biopsied Liver Tissue.: Ji Yoon Bae, Hyung Kyung Kim, Hanna Kang, Ha Rin Cheong, Dong Eun Song, Sun Hee Sung, Heasoo Koo, Woon Sup Han, Jeong Kyong Lee, Tae Hun Kim, Kyu Won Chung, Min Sun Cho; Korean J Pathol. 2010;44(2):132-140.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.2.132

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Abstract PDF

BACKGROUND
Regulatory T cells (Tregs) may contribute to the immunological hyporesponsiveness against hepatitis B virus (HBV), and this can result in chronic infection. Tregs suppress the T cell responses directed against HBV and they protect hepatocytes by down-regulating the immune responses that cause liver damage, but the role of Tregs has not been well characterized.
METHODS
Fifty four patients were selected and classified into three groups (12 were in the immune-tolerance phase, 35 were in the immune-clearance phase and 7 were in the asymptomatic virus carrier phase). We examined the frequency of CD3+, CD4+ & CD8+ T cells and forkhead box P3 (FoxP3)+ Tregs in the needle-biopsied liver tissue by performing immunohistochemistry.
RESULTS
The FoxP3+ Tregs were mainly located at the portal tracts. In the immune-clearance phase, the frequency of FoxP3+ Tregs was significantly increased compared to that of the immune-tolerance group and the asymptomatic carrier group. Increased FoxP3+ T cells were observed in the patients with a higher histologic inflammatory index. No correlation was observed among the numbers of FoxP3+ Tregs, the serum alanine aminotransferase level, detection of HBeAg and the HBV-DNA viral load.
CONCLUSIONS
FoxP3+ Tregs may play important roles in suppressing the immune response to HBV and the complete elimination of HBV.

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Significance of Foxp3 Positive Regulatory T Cell and Tumor Infiltrating T Lymphocyte in Triple Negative Breast Cancer
Hanna Kang, Harin Cheong, Min Sun Cho, Heasoo Koo, Woon Sup Han, Kyung Eun Lee, Byung In Moon, Sun Hee Sung
The Korean Journal of Pathology.2011; 45(1): 53. CrossRef

The Prognostic Significance of the Tumor-Infiltrating FoxP3-Positive Regulatory T Cells in Gastric Carcinoma.: Sang Jae Noh, Shin Young Park, Kyung Ryoul Kim, Chan Young Kim, Keun Sang Kwon, Ho Sung Park, Ho Lee, Myoung Ja Chung, Woo Sung Moon, Kyu Yun Jang; Korean J Pathol. 2010;44(1):9-15.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.1.9

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Abstract PDF

BACKGROUND
Regulatory T cells (Tregs) are known to be key regulators of immune responses in patients with autoimmune disease and infection and also for attenuating antitumor immunity by the host. It has been reported that high numbers of tumor-infiltrating Tregs might be associated with poor clinical outcomes for several malignant tumors. Therefore, this study aimed to examine the impact of tumor-infiltrating Tregs on the prognosis of gastric carcinoma patients.
METHODS
The immunohistochemical staining for anti-fork head Box P3 (FoxP3) antibody was performed by using a 3 mm core from the tumor specimens of each of the 173 gastric cancer patients for constructing a tissue microarray. FoxP3-positive Tregs were quantified by calculating the numbers of positive cells per 5 high-power fields on light microscopy. Thereafter, the 173 patients were subdivided into the low Tregs group (< or = 3/5 high power fields [HPF], n = 41) and the high Tregs group (> 3/5 HPF, n = 132).
RESULTS
The high Tregs group was significantly associated with a higher stage, more invasion depth and lymph node metastasis (p = 0.009, p = 0.036, p = 0.006, respectively). The high Tregs group showed significantly poorer overall survival and event-free survival (p = 0.004, p = 0.017, respectively) on the univariate analysis. The Tregs group and the tumor, node and metastasis stage were also independent prognostic factors that were significantly associated with overall survival (p = 0.025, p < 0.001, respectively) by multivariate analysis.
CONCLUSIONS
Our results indicated that a high number of tumor-infiltrating FoxP3-positive Tregs could be an indicator of poor long term survival for gastric carcinoma patients.

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Tumor-infiltrating PD1-Positive Lymphocytes and FoxP3-Positive Regulatory T Cells Predict Distant Metastatic Relapse and Survival of Clear Cell Renal Cell Carcinoma
Myoung Jae Kang, Kyoung Min Kim, Jun Sang Bae, Ho Sung Park, Ho Lee, Myoung Ja Chung, Woo Sung Moon, Dong Geun Lee, Kyu Yun Jang
Translational Oncology.2013; 6(3): 282. CrossRef
Significance of Foxp3 Positive Regulatory T Cell and Tumor Infiltrating T Lymphocyte in Triple Negative Breast Cancer
Hanna Kang, Harin Cheong, Min Sun Cho, Heasoo Koo, Woon Sup Han, Kyung Eun Lee, Byung In Moon, Sun Hee Sung
The Korean Journal of Pathology.2011; 45(1): 53. CrossRef

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