Differences in immune-related gene expressions and tumor-infiltrating lymphocytes according to chemotherapeutic response in ovarian high-grade serous carcinoma

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.

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

Journal of the Egyptian National Cancer Institute ◽

10.1186/s43046-021-00073-5 ◽

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.

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Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma

Oncotarget ◽

10.18632/oncotarget.6429 ◽

2015 ◽

Vol 7 (2) ◽

pp. 1486-1499 ◽

Cited By ~ 122

Author(s):

Silvia Darb-Esfahani ◽

Catarina Alisa Kunze ◽

Hagen Kulbe ◽

Jalid Sehouli ◽

Stephan Wienert ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Cancer Cells ◽

Tumor Infiltrating Lymphocytes ◽

Serous Carcinoma ◽

Prognostic Impact ◽

High Grade ◽

Programmed Cell Death 1 ◽

Infiltrating Lymphocytes

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Touching Tumor‐Infiltrating Lymphocytes in Low Risk Ductal Carcinoma in Situ Correlates with Upgrade to High Grade DCIS

Histopathology ◽

10.1111/his.14539 ◽

2021 ◽

Author(s):

Thaer Khoury ◽

Marie Quinn ◽

Wanqing Tian ◽

Li Yan ◽

Haiying Zhan

Keyword(s):

Ductal Carcinoma In Situ ◽

Carcinoma In Situ ◽

Ductal Carcinoma ◽

Tumor Infiltrating Lymphocytes ◽

Low Risk ◽

High Grade ◽

Infiltrating Lymphocytes

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Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

JAMA Oncology ◽

10.1001/jamaoncol.2017.3290 ◽

2017 ◽

Vol 3 (12) ◽

pp. e173290 ◽

Cited By ~ 90

Author(s):

◽

Ellen L. Goode ◽

Matthew S. Block ◽

Kimberly R. Kalli ◽

Robert A. Vierkant ◽

...

Keyword(s):

Ovarian Cancer ◽

Survival Time ◽

Dose Response ◽

Tumor Infiltrating Lymphocytes ◽

High Grade ◽

Serous Ovarian Cancer ◽

Infiltrating Lymphocytes

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Nomograms to Predict the Density of Tumor-Infiltrating Lymphocytes in Patients With High-Grade Serous Ovarian Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.590414 ◽

2021 ◽

Vol 11 ◽

Author(s):

Danian Dai ◽

Lili Liu ◽

He Huang ◽

Shangqiu Chen ◽

Bo Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

Menopausal Status ◽

Tumor Infiltrating Lymphocytes ◽

Roc Curves ◽

Clinicopathological Characteristics ◽

High Grade ◽

Serous Ovarian Cancer ◽

Ki 67 ◽

Infiltrating Lymphocytes

BackgroundTumor-infiltrating lymphocytes (TILs) have important roles in predicting tumor therapeutic responses and progression, however, the method of evaluating TILs is complicated. We attempted to explore the association of TILs with clinicopathological characteristics and blood indicators, and to develop nomograms to predict the density of TILs in patients with high-grade serous ovarian cancer (HGSOC).MethodsThe clinical profiles of 197 consecutive postoperative HGSOC patients were retrospectively analyzed. Tumor tissues and matched normal fallopian tubes were immunostained for CD3+, CD8+, and CD4+ T cells on corresponding tissue microarrays and the numbers of TILs were counted using the NIH ImageJ software. The patients were classified into low- or high-density groups for each marker (CD3, CD4, CD8). The associations of the investigated TILs to clinicopathological characteristics and blood indicators were assessed and the related predictors for densities of TILs were used to develop nomograms; which were then further evaluated using the C-index, receiver operating characteristic (ROC) curves and calibration plots.ResultsMenopausal status, estrogen receptor (ER), Ki-67 index, white blood cell (WBC), platelets (PLT), lactate dehydrogenase (LDH), and carbohydrate antigen 153 (CA153) had significant association with densities of tumor-infiltrating CD3+, CD8+, or CD4+ T cells. The calibration curves of the CD3+ (C-index = 0.748), CD8+ (C-index = 0.683) and CD4+ TILs nomogram (C-index = 0.759) demonstrated excellent agreement between predictions and actual observations. ROC curves of internal validation indicated good discrimination for the CD8+ TILs nomogram [area under the curve (AUC) = 0.659, 95% CI 0.582–0.736] and encouraging performance for the CD3+ (AUC= 0.708, 95% CI 0.636–0.781) and CD4+ TILs nomogram (AUC = 0.730, 95% CI 0.659–0.801).ConclusionMenopausal status, ER, Ki-67 index, WBC, PLT, LDH, and CA153 could reflect the densities of T cells in the tumor microenvironment. Novel nomograms are conducive to monitor the immune status of patients with HGSOC and help doctors to formulate the appropriate treatment strategies.

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