Journal of Pathology and Translational Medicine

Original Articles

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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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.

Citations

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Daniel S. Lefler, Steven A. Manobianco, Babar Bashir
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Ananthan Sadagopan, Theodoros Michelakos, Gabriella Boyiadzis, Cristina Ferrone, Soldano Ferrone
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Pu Yu, Lili Zhu, Kang Cui, Yabing Du, Chaojie Zhang, Wang Ma, Jia Guo
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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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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.

Citations

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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.

Citations

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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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