Correlation of mesothelin expression and CD8 tumor infiltrating lymphocytes with prognosis in cholangiocarcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15650-e15650
Author(s):  
Paul Raymond Kunk ◽  
Joseph Mounir Obeid ◽  
Kevin Winters ◽  
Patcharin Pramoonjago ◽  
Dirk G. Brockstedt ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Cells ◽  
Regression Tree ◽  
Tumor Infiltrating Lymphocytes ◽  
Classification And Regression Tree ◽  
Rank Test ◽  
Risk Of Death ◽  
Unmet Treatment Need ◽  
Infiltrating Lymphocytes ◽  
Mesothelin Expression

e15650 Background: Cholangiocarcinoma (CC) is a rapidly progressing malignancy with an unmet treatment need. Little is known about the CC tumor immune microenvironment or about relevant antigenic targets. We hypothesized that lack of T cell infiltration or PD-L1 expression may identify patients at high risk of death, and that mesothelin may be a relevant antigenic target. Methods: A retrospective analysis was conducted of CC tumors at the University of Virginia from 2000-2014. TMAs were constructed of 3-4 cores from each tumor and were stained by IHC for CD4 and CD8 tumor infiltrating lymphocytes (TILs), mesothelin and PD-L1. TMAs were scanned using the Leica SCN400 and analyzed using the Digital Image Hub software. Stain intensity thresholds for defining positive cells were determined by two users and recorded as an average of all cores from each tumor. Mesothelin and PD-L1 expression were measured as a percentage of positive tumor cells. TILs and protein expression were analyzed for association with overall survival, grouped as high or low expression based either on the median or the 33rdpercentile. Correlation with overall survival was assessed using a log rank test and a classification and regression tree with p-values < 0.05 being considered statistically significant. Results: Ninety-nine tumors were available for analysis: 26 intrahepatic, 37 hilar, and 36 distal. PD-L1 and mesothelin expression > 1% of tumor cells were found in 16% and 92% of tumors, respectively. CD4 and CD8 TILs were found in nearly all tumors (98% and 96%), with the majority showing intraepithelial CD4 and CD8 infiltration (73% and 68%). There were no significant associations between survival and PD-L1, mesothelin, or CD4 and CD8 infiltration. However when considered together, the group with low mesothelin/low CD8 (each below 33rdpercentile) had worse survival (9.1 months) compared to high mesothelin/high CD8 (25 months), high mesothelin/low CD8 (30.1 months) and low mesothelin/high CD8 (26.1 months), p = 0.015. Conclusions: CC tumors that lack CD8 infiltration and mesothelin expression have a poor prognosis. Mesothelin represents an attractive target in cholangiocarcinoma, opening the door for future immunotherapy for CC.

Thresholding of prominent biomarkers of breast cancer on overall survival using classification and regression tree

2021 ◽  
pp. 1-10
Author(s):  
Pragya Kumari ◽  
Gajendra K. Vishwakarma ◽  
Atanu Bhattacharjee
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Survival Analysis ◽  
Regression Tree ◽  
Vital Role ◽  
Classification And Regression Tree ◽  
Brier Score ◽  
Risk Of Death ◽  
Cart Analysis ◽  
Classification And Regression

BACKGROUND: HER2, ER, PR, and ERBB2 play a vital role in treating breast cancer. These are significant predictive and prognosis biomarkers of breast cancer. OBJECTIVE: We aim to obtain a unique biomarker-specific prediction on overall survival to know their survival and death risk. METHODS: Survival analysis is performed on classified data using Classification and Regression Tree (CART) analysis. Hazard ratio and Confidence Interval are computed using MLE and the Bayesian approach with the CPH model for univariate and multivariable illustrations. Validation of CART is executed with the Brier score, and accuracy and sensitivity are obtained using the k-nn classifier. RESULTS: Utilizing CART analysis, the cut-off value of continuous-valued biomarkers HER2, ER, PR, and ERBB2 are obtained as 14.707, 8.128, 13.153, and 6.884, respectively. Brier score of CART is 0.16 towards validation of methodology. Survival analysis gives a demonstration of the survival estimates with significant statistical strategies. CONCLUSIONS: Patients with breast cancer are at low risk of death, whose HER2 value is below its cut-off value, and ER, PR, and ERBB2 values are greater than their cut-off values. This comparison is with the patient having the opposite side of these cut-off values for the same biomarkers.

Correlation of β-catenin expression in non-small cell lung cancer to prognosis and CD8 positive cells infiltration.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 142-142
Author(s):  
Satoshi Muto ◽  
Yuki Ozaki ◽  
Takuya Inoue ◽  
Takumi Yamaura ◽  
Mitsuro Fukuhara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Tumor Cells ◽  
Cell Lung Cancer ◽  
Progression Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Small Cell ◽  
Rank Test ◽  
Small Cell Lung ◽  
Infiltrating Lymphocytes

142 Background: It was reported that β-catenin expression in tumor cells suppresses dendritic cell infiltration into tumor in mouse model of melanoma. It results in less of tumor infiltrating lymphocytes. In non-small cell lung cancer (NSCLC), it is not well understood that β-catenin is involved in cancer immunity in that context. Methods: We studied the association between β-catenin expression and CD8 positive cells infiltration in NSCLC. Ninety-one patients with NSCLC who had complete surgical resection during January 2013 to June 2015 were subjected. β-catenin expression of tumor cells and CD8 positive cells infiltration were analyzed by immunohistochemistry. Survival analysis including over-all survival (OS) and progression-free survival (PFS) were also statistically examined by log-rank test. Results: Fourteen cases (15%) were β-catenin positive. Among 14 β-catenin positive cases, only 2 cases (14%) had CD8 positive cells infiltration. Seventy-five cases (97%) had CD8 positive cells infiltration in β-catenin negative tumors (p < 0.01). Squamous cell carcinoma was relatively higher level of expression than others (44% vs. 9%) and mean primary tumor size was larger in β-catenin positive tumors (3.6 cm) than those in negative tumors (2.7 cm). Median OS was 43.8 months and median PFS was 37.0 months in β-catenin positive group. They were not reached in β-catenin negative group. Both OS and PFS were shorter in β-catenin positive cases (p < 0.01). Conclusions: In NSCLC, β-catenin expression was negatively associated with CD8 positive cells infiltration and poor prognosis. We furthermore will focus on the association between β-catenin expression in tumor and clinical efficacy or resistant mechanism of immune checkpoint blockades.

scholarly journals Overexpression of an Immune Checkpoint (CD155) in Breast Cancer Associated with Prognostic Significance and Exhausted Tumor-Infiltrating Lymphocytes: A Cohort Study

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Yu-Chen Li ◽  
Quan Zhou ◽  
Qing-Kun Song ◽  
Rui-Bin Wang ◽  
Shuzhen Lyu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Cohort Study ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Prognostic Significance ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Microenvironment ◽  
Infiltrating Lymphocytes ◽  
Low Expression

Purpose. The immune checkpoint inhibitor is approved for breast cancer treatment, but the low expression of PD-L1 limits the immunotherapy. CD155 is another immune checkpoint protein in cancers and interacts with ligands to regulate immune microenvironment. This study is aimed at investigating the expression of CD155 and the association with prognosis and pathological features of breast cancer. Methods. 126 patients were recruited this cohort study consecutively, and CD155 expression on tumor cells was detected by immunohistochemistry. The Kaplan-Meier survival curve and Cox hazard regression model were used to estimate the association. Results. 38.1% patients had an overexpression of CD155, and the proportion of tumor cells with CD155 overexpression was 17%, 39%, 37%, and 62% among Luminal A, Luminal B, HER2-positive, and triple negative breast cancer cases, respectively (p<0.05). Patients with CD155 overexpression had the Ki-67 index significantly higher than that of patients with low expression (42% vs. 26%). Though the number of tumor-infiltrating lymphocytes was higher among patients with CD155 overexpression (144/HPF vs. 95/HPF), the number of PD-1+ lymphocytes was significantly higher (52/HPF vs. 25/HPF, p<0.05). Patients of CD155 overexpression had the disease-free and overall survival decreased by 13 months and 9 months, respectively (p<0.05). CD155 overexpression was associated with an increased relapse (HR=13.93, 95% CI 2.82, 68.91) and death risk for breast cancer patients (HR=5.47,1.42,20.99). Conclusions. Overexpression of CD155 was correlated with more proliferative cancer cells and a dysfunctional immune microenvironment. CD155 overexpression introduced a worse relapse-free and overall survival and might be a potential immunotherapy target for breast cancer.

scholarly journals Programmed death ligand-1 and CD8 tumor-infiltrating lymphocytes (TILs) as prognostic predictors in ovarian high-grade serous carcinoma (HGSC)

2021 ◽  
Vol 33 (1) ◽  
Author(s):  
Mayada Saad Farrag ◽  
Khaled Abdelwahab ◽  
Nesrine Saad Farrag ◽  
Waleed Elsayed Elrefaie ◽  
Ziad Emarah
Keyword(s):  
Overall Survival ◽  
Tumor Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Residual Tumor ◽  
Serous Carcinoma ◽  
High Grade ◽  
Tumor Immune Escape ◽  
Prognostic Effect ◽  
Significant Difference ◽  
Infiltrating Lymphocytes

Abstract Background P D-L1 is expressed in tumor cells and plays a crucial role in tumor immune escape. Tumor-infiltrating lymphocytes (TILs) as CD8 T cells contribute to reduced tumor growth. Few studies investigated the prognostic effect of PD-L1 and CD8 TILs in ovarian high-grade serous carcinoma (HGSC). In the present study, we analyzed the expression of PD-L1 and CD8 TILs in HGSC by immunohistochemistry, and results were correlated to prognosis. It was carried on 54 cases of ovarian HGSC who attended the Oncology Centre, Mansoura University, Egypt, from 2012 till 2019. Results Nearly 60% of cases showed positive PD-L1 expression in tumor cells. Regarding the clinicopathological characteristics, higher PD-L1 expression was found among patients with residual tumor (82.4%) compared to patients with no residual tumor (54.5%), with marginal statistical significance (p 0.07). PD-L1 was significantly associated with CD8 TILs expression. Higher PD-L1 expression was found among tumors with low expression of CD8 TILs with statistically significant difference (p≤0.001). Disease-free survival (DFS) was significantly lower among the group with positive expression of PD-L1 compared to the group with negative expression of PD-L1 (p 0.01), while overall survival (OS) was not associated with PD-L1 expression. On the other hand, the overall survival (OS) in patients with high CD8 expression was significantly higher than patients with low CD8 expression (p 0.043), while DFS was not significantly different among both CD8 TILS groups. Conclusions PD-L1 and CD8 TILs may become a promising therapeutic target for patients with ovarian HGSC. More studies are needed to further validate their prognostic effect. Precise identification of patients who will benefit from PD-L1 checkpoint blockade and TILs adaptive immunotherapy is mandatory.

scholarly journals Tumor-Infiltrating Lymphocytes and Cancer Markers in Osteosarcoma: Influence on Patient Survival

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6075
Author(s):  
José Manuel Casanova ◽  
Jani-Sofia Almeida ◽  
John David Reith ◽  
Luana Madalena Sousa ◽  
Ruben Fonseca ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Cells ◽  
Strong Association ◽  
Tumor Biology ◽  
Progression Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Response To Therapy ◽  
Cd4 Cells ◽  
Free Survival ◽  
Infiltrating Lymphocytes

Osteosarcoma (OST) is the most common type of high-grade primary bone tumor, which mainly affects young adults. The current standard of care for OST combines surgical resection with chemotherapy. The clinical outcomes and the current options to treat OST patients are unsatisfactory and novel treatment strategies are needed. The crosstalk between tumor cells and immune cells is essential to the OST microenvironment. Despite the efforts that have been made to address the importance of immune-related factors in OST, there is still a lot to understand. The purpose of the current study was to evaluate the tumor-infiltrating lymphocytes (TIL), the expression of proteins involved in tumor biology, and their impact on the clinical outcome of OST patients. We studied 93 samples of OST patients using immunohistochemistry and histomorphometry. We looked for the infiltration of CD3+, CD4+, CD8+, TIA1+ and CD20+ cells and for the expression of CD44 standard (CD44s) and variant 6 (CD44v6), CD95/Fas, Fas-L, p53 and p-glycoprotein. All the parameters were analyzed for the influence on the occurrence of death and metastasis, plus patient overall survival (OS) and progression-free survival (PFS). The effect of sex, age, tumor location (distal femur or proximal tibia) and the combination with neoadjuvant chemotherapy was also assessed. Our results suggest that the presence of tumor-infiltrating CD4+ cells provides protection to OST patients, and that CD8+ cells have a significant impact on the patient’s overall survival (OS) and progression-free survival (PFS), which is more evident in male patients. In addition, a strong association between tumor-infiltrating CD4+ cells and the presence of CD44s expression in tumor samples was observed. Analysis of TIL and tumor markers related to tumor biology could be useful to stratify patients and monitor the response to therapy, as well as to assist with the development of immunotherapy strategies to improve the effects of cytotoxic TIL to eradicate the tumor cells.

scholarly journals Improving Risk Stratification of Early Oral Tongue Cancer with TNM-Immune (TNM-I) Staging System

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3235
Author(s):  
Alhadi Almangush ◽  
Ibrahim O. Bello ◽  
Ilkka Heikkinen ◽  
Jaana Hagström ◽  
Caj Haglund ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tongue Cancer ◽  
Early Stage ◽  
Disease Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Staging System ◽  
Oral Tongue ◽  
Oral Tongue Cancer ◽  
Important Player ◽  
Infiltrating Lymphocytes

Although patients with early-stage oral tongue squamous cell carcinoma (OTSCC) show better survival than those with advanced disease, there is still a number of early-stage cases who will suffer from recurrence, cancer-related mortality and worse overall survival. Incorporation of an immune descriptive factor in the staging system can aid in improving risk assessment of early OTSCC. A total of 290 cases of early-stage OTSCC re-classified according to the American Joint Committee on Cancer (AJCC 8) staging were included in this study. Scores of tumor-infiltrating lymphocytes (TILs) were divided as low or high and incorporated in TNM AJCC 8 to form our proposed TNM-Immune system. Using AJCC 8, there were no significant differences in survival between T1 and T2 tumors (p > 0.05). Our proposed TNM-Immune staging system allowed for significant discrimination in risk between tumors of T1N0M0-Immune vs. T2N0M0-Immune. The latter associated with a worse overall survival with hazard ratio (HR) of 2.87 (95% CI 1.92–4.28; p < 0.001); HR of 2.41 (95% CI 1.26–4.60; p = 0.008) for disease-specific survival; and HR of 1.97 (95% CI 1.13–3.43; p = 0.017) for disease-free survival. The TNM-Immune staging system showed a powerful ability to identify cases with worse survival. The immune response is an important player which can be assessed by evaluating TILs, and it can be implemented in the staging criteria of early OTSCC. TNM-Immune staging forms a step towards a more personalized classification of early OTSCC.

scholarly journals Predicted CD4+ T cell infiltration levels could indicate better overall survival in sarcoma patients

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098153
Author(s):  
Qing Bi ◽  
Yang Liu ◽  
Tao Yuan ◽  
Huizhen Wang ◽  
Bin Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Survival Data ◽  
Tumor Infiltrating Lymphocytes ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Whole Exome ◽  
Cancer Genome Atlas ◽  
Infiltrating Lymphocytes

Objective The role of tumor-infiltrating lymphocytes (TILs) has not yet been characterized in sarcomas. The aim of this bioinformatics study was to explore the effect of TILs on sarcoma survival and genome alterations. Methods Whole-exome sequencing, transcriptome sequencing, and survival data of sarcoma were obtained from The Cancer Genome Atlas. Immune infiltration scores were calculated using the Tumor Immune Estimation Resource. Potential associations between abundance of infiltrating TILs and survival or genome alterations were examined. Results Levels of CD4+ T cell infiltration were associated with overall survival of patients with pan-sarcomas, and higher CD4+ T cell infiltration levels were associated with better survival. Somatic copy number alterations, rather than mutations, were found to correlate with CD4+ T cell infiltration levels. Conclusions This data mining study indicated that CD4+ T cell infiltration levels predicted from RNA sequencing could predict sarcoma prognosis, and higher levels of CD4+ T cells infiltration indicated a better chance of survival.

scholarly journals iNOS Expression by Tumor-Infiltrating Lymphocytes, PD-L1 and Prognosis in Non-Small-Cell Lung Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3276
Author(s):  
Alexandra Giatromanolaki ◽  
Avgi Tsolou ◽  
Eleftheria Daridou ◽  
Maria Kouroupi ◽  
Katerina Chlichlia ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Small Cell Lung Carcinoma ◽  
Expression Patterns ◽  
Tumor Infiltrating Lymphocytes ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tissue Samples ◽  
Cell Lung Carcinoma ◽  
Infiltrating Lymphocytes

Background: Inducible Nitric Oxygen Synthase (iNOS) promotes the generation of NO in tissues. Its role in tumor progression and immune response is unclear. Methods: The immunohistochemical expression patterns of iNOS were studied in a series of 98 tissue samples of non-small-cell lung carcinoma (NSCLC), in parallel with the expression of hypoxia and anaerobic metabolism markers, PD-L1 and tumor-infiltrating lymphocytes (TILs). Results: iNOS is expressed by cancer cells in 19/98 (19.4%), while extensive expression by cancer-associated fibroblasts occurs in 8/98 (8.2%) cases. None of these patterns relate to stage or prognosis. Extensive infiltration of the tumor stroma by iNOS-expressing TILs (iNOS+TILs) occurs in 47/98 (48%) cases. This is related to low Hypoxia-Inducible Factor 1α (HIF1α), high PD-L1 expression and a better overall survival (p = 0.002). Expression of PD-L1, however, mitigates the beneficial effect of the presence of iNOS+TIL. Conclusions: Extensive expression of iNOS by TILs occurs in approximately 50% of NSCLCs, and this is significantly related to an improved overall survival. This brings forward the role of iNOS in anti-neoplastic lymphocyte biology, supporting iNOS+TILs as a putative marker of immune response. The value of this biomarker as a predictive and treatment-guiding tool for tumor immunotherapy demands further investigation.

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