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.

Should All Cases of High-Grade Serous Ovarian, Tubal, and Primary Peritoneal Carcinomas Be Reclassified as Tubo-Ovarian Serous Carcinoma?

2015 ◽  
Vol 25 (7) ◽  
pp. 1201-1207 ◽  
Author(s):  
Esther Louise Moss ◽  
Tim Evans ◽  
Philippa Pearmain ◽  
Sarah Askew ◽  
Kavita Singh ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clear Cell ◽  
Stage Iii ◽  
Serous Carcinoma ◽  
Low Grade ◽  
Type I ◽  
High Grade ◽  
Type Ii ◽  
Ovarian Serous Carcinoma ◽  
Significant Difference

IntroductionThe dualistic theory of ovarian carcinogenesis proposes that epithelial “ovarian” cancer is not one entity with several histological subtypes but a collection of different diseases arising from cells of different origin, some of which may not originate in the ovarian surface epithelium.MethodsAll cases referred to the Pan-Birmingham Gynaecological Cancer Centre with an ovarian, tubal, or primary peritoneal cancer between April 2006 and April 2012 were identified from the West Midlands Cancer Registry. Tumors were classified into type I (low-grade endometrioid, clear cell, mucinous, and low-grade serous) and type II (high-grade serous, high-grade endometrioid, carcinosarcoma, and undifferentiated) cancers.ResultsOvarian (83.5%), tubal (4.3%), or primary peritoneal carcinoma (12.2%) were diagnosed in a total of 583 woman. The ovarian tumors were type I in 134 cases (27.5%), type II in 325 cases (66.7%), and contained elements of both type I and type II tumors in 28 cases (5.7%). Most tubal and primary peritoneal cases, however, were type II tumors: 24 (96.0%) and 64 (90.1%), respectively. Only 16 (5.8%) of the ovarian high-grade serous carcinomas were stage I at diagnosis, whereas 240 (86.6%) were stage III+. Overall survival varied between the subtypes when matched for stage. Stage III low-grade serous and high-grade serous carcinomas had a significantly better survival compared to clear cell and mucinous cases,P= 0.0134. There was no significant difference in overall survival between the high-grade serous ovarian, tubal, or peritoneal carcinomas when matched for stage (stage III,P= 0.3758; stage IV,P= 0.4820).ConclusionsType II tumors are more common than type I and account for most tubal and peritoneal cancers. High-grade serous carcinomas, whether classified as ovarian/tubal/peritoneal, seem to behave as one disease entity with no significant difference in survival outcomes, therefore supporting the proposition of a separate classification of “tubo-ovarian serous carcinoma”.

scholarly journals Development and Validation of a Prognostic Autophagy-Related Gene Pair Index Related to Tumor-Infiltrating Lymphocytes in Early-Stage Lung Adenocarcinoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Zi-Hao Wang ◽  
Yu Li ◽  
Pei Zhang ◽  
Xuan Xiang ◽  
Xiao-Shan Wei ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Gene Pair ◽  
Early Stage ◽  
Tumor Infiltrating Lymphocytes ◽  
Related Gene ◽  
Tumor Immune Escape ◽  
Cox Regression Analysis ◽  
Significant Difference ◽  
Infiltrating Lymphocytes

The role of autophagy in lung cancer is context-dependent and complex. Recent studies have reported the important role of autophagy in tumor immune escape. However, the association between autophagy and tumor-infiltrating lymphocytes (TILs) in early-stage lung adenocarcinoma (LUAD) remains unclear. In this study, we aimed to develop and validate the autophagy-related gene pair index (ATGPI) and autophagy clinical prognostic index (ACPI) in multiple LUAD cohorts, including The Cancer Genome Atlas (TCGA) cohort, Gene Expression Omnibus cohorts, and one cohort from Union Hospital, Wuhan (UH cohort), using a Cox proportional hazards regression model with the least absolute shrinkage and selection operator. Multivariate Cox regression analysis demonstrated that there was a significant difference in overall survival (OS) between patients with high and low ATGPI in the testing [hazard ratio (HR) = 1.97; P < 0.001] and TCGA validation (HR = 2.25; P < 0.001) cohorts. Time-dependent receiver operating characteristic curve analysis was also performed. We found that high ATGPI could accurately identify patients with early-stage LUAD with shorter OS, with the areas under the curve of 0.703 and 0.676 in the testing and TCGA validation cohorts, respectively. Concordance index (C-index) was used to evaluate the efficiency of ATGPI and ACPI. The C-index of ACPI was higher than that of ATGPI in the testing (0.71 vs. 0.66; P < 0.001), TCGA validation (0.69 vs. 0.65; P = 0.028), and UH (0.80 vs. 0.70; P = 0.015) cohorts. TIL analysis demonstrated that the proportions of tumor-infiltrating CD4+ T cells were lower in the high-ATGPI group than in the low-ATGPI group in both the TCGA validation and UH cohorts. These results indicate the potential clinical use of ATG signatures which are associated with TILs, in identifying patients with early-stage LUAD with different OS.

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.

The integration of proportion and cell counts of stromal, not intratumoral, PD-1+ tumor-infiltrating lymphocytes has prognostic significance in esophageal squamous cell carcinoma

2020 ◽  
Author(s):  
Qingkun Song ◽  
Feng Shi ◽  
Shuo Xiao ◽  
Yuchen Li ◽  
Yanjie Zhao ◽  
...  
Keyword(s):  
Overall Survival ◽  
Esophageal Cancer ◽  
Cancer Patients ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
High Power Field ◽  
Prognostic Effect ◽  
Cell Counts ◽  
Infiltrating Lymphocytes

Summary The present study aimed to investigate the prognostic effect of intratumoral and stromal exhausted tumor-infiltrating lymphocytes (TILs) on operable esophageal cancer patients. We performed a retrospective cohort study by consecutively recruiting 142 patients with esophageal cancer. The proportion and cell counts of intratumoral and stromal PD-1+ TILs in tumor microenvironment were independently evaluated by two pathologists. Neither proportion nor cell counts of intratumoral PD-1+ TILs was associated with prognosis (p &gt; 0.05). However, patients with the proportion of stromal PD1+ TILs &gt;20% had the median overall survival (OS) at 19 months, significantly longer than those with the proportion = 20%. The adjusted hazard ratio (HR) was 1.49 (95%CI 0.82, 2.69). Patients with cell counts of stromal PD1+ TILs = 18/ high-power field (HPF) had the median disease-free survival (DFS) at 10 months. However, patients with cell counts&gt;18/HPF had the median DFS at 48 months (p = 0.037), and the adjusted HR was 0.59 (95%CI 0.35, 1.01). Compared with patients with proportion = 20% and cell counts &gt;18/HPF of stromal PD1+ TILs, patients with proportion = 20% and cell counts = 18/HPF, proportion &gt;20% and cell counts &gt;18/HPF, and proportion &gt;20% and cell counts = 18/HPF, had the adjusted HRs increased to 3.73, 3.36 and 3.99 for DFS (p for trend being 0.030) and the adjusted HRs increased to 2.95, 3.64 and 3.82 (p for trend being 0.015) for OS, respectively. The integration of proportion and cell counts of PD-1+ stromal TILs has a significant association with the relapse and overall survival of esophageal cancer patients. Further prospective studies are warranted.

scholarly journals Characterization of immunoreactivity with whole-slide imaging and digital analysis in high-grade serous ovarian cancer

Tumor Biology ◽  
2020 ◽  
Vol 42 (11) ◽  
pp. 101042832097140
Author(s):  
Tiina Jäntti ◽  
Satu Luhtala ◽  
Johanna Mäenpää ◽  
Synnöve Staff
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Granzyme B ◽  
Progression Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Serous Carcinoma ◽  
High Grade ◽  
Whole Slide Imaging ◽  
Free Survival ◽  
Infiltrating Lymphocytes

Ovarian cancer is the most lethal of gynecological cancers with 5-year survival rate of ca. 45%. The most common histologic subtype is high-grade serous carcinoma, which typically is presented with advanced stage and development of chemoresistance. Therefore, new treatment options, including immunotherapies, are needed. Understanding the features of the immune cell populations in the tumor microenvironment is essential for developing personalized treatments and finding predictive biomarkers. Digital image analysis may enhance the accuracy and reliability of immune cell infiltration assessment in the tumor microenvironment. The aim of this study was to characterize tumor microenvironment in a retrospective cohort of high-grade serous carcinoma samples with whole-slide imaging and digital image analysis. Formalin-fixed paraffin-embedded high-grade serous carcinoma tumor tissue samples (n = 67) were analyzed for six immunohistochemical stainings: CD4, CD8, FoxP3, granzyme B, CD68, and CD163. The stained sample slides were scanned into a digital format and assessed using QuPath 0.1.2 and ImageJ software. Staining patterns were associated with clinicopathological data. The higher numbers of intraepithelial CD8+, CD163+, and granzyme B+ immune cells were associated with survival benefit when analyzed individually, while high levels of both CD8+ and granzyme B+ tumor-infiltrating lymphocytes were an independent prognostic factor in the Cox multivariate regression analysis (median progression-free survival; hazard ratio = 0.287, p = 0.002). Specimens taken after administration of neoadjuvant chemotherapy presented with lower FoxP3+ tumor-infiltrating lymphocyte density (Fisher’s exact test, p = 0.013). However, none of the studied immunomarkers was associated with overall survival or clinical factors. Tumors having high amount of both intraepithelial CD8+ and granzyme B+ tumor-infiltrating lymphocytes showed better progression-free survival, possibly reflecting an activated immune state in the tumor microenvironment. The combined positivity of CD8 and granzyme B warrants further investigation with respect to predicting response to immune therapy. Neoadjuvant chemotherapy may have an effect on the tumor microenvironment and therefore on the response to immuno-oncologic or chemotherapy treatments.

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 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.

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