Expression and Significance of Immune Checkpoints in Clear Cell Carcinoma of the Uterine Cervix

Abstract

The purpose of this study was to investigate the expression levels of the immune checkpoint proteins, programmed cell death-ligand 1 (PD-L1), B7-H3, B7-H4, and V-domain Ig suppressor of T cell activation (VISTA), as well as the significance thereof, in clear cell carcinoma (CCC) of the cervix (a rare histological subtype of cervical cancer). We also compared the expression statuses of these biomarkers in cervical CCCs with those in cervical squamous cell carcinomas (SCCs). We evaluated the expression of PD-L1, B7-H3, B7-H4, and VISTA in 50 cervical CCCs and 100 SCCs using immunohistochemical staining and investigated the associations between these markers, clinicopathologic features, and survival in patients with CCCs. Of the cervical CCC samples examined, 22%, 16%, 32%, and 34% were positive for PD-L1, B7-H3, B7-H4, and VISTA, respectively. Nineteen samples (38%) were negative for all 4 of these markers, whereas 31 (62%) expressed at least 1 marker. None of these markers was associated with the investigated clinicopathologic variables or patient survival. PD-L1, B7-H3, and VISTA were observed significantly more frequently in SCCs than in CCCs of the cervix. Our study confirmed the expression of immune checkpoint proteins in cervical CCCs and indicated their nonredundant and complementary roles. As such, our data suggest that monotherapeutic immune checkpoint blockade may not be sufficiently effective in patients with cervical CCC.

Expression of B7-H3 Correlates with PD-L1 and Poor Prognosis in Patients with Cervical Cancer

“…Immunohistochemistry was performed using our laboratory protocol as described previously. 14 , 17 , 26 Briefly, 4 μm TMA serial sections were deparaffinized and subjected to heat-induced epitope retrieval with 10 mM sodium citrate (pH 6.0) at 95°C for 20 min. The endogenous peroxidase activity was quenched using a 0.3% hydrogen peroxide solution.…”

“…Immunohistochemistry was performed using our laboratory protocol as described previously. 14,17,26 Briefly, 4 https://doi.org/10.2147/OTT.S318082…”

“…6 B7-H3 protein is present at low levels in the liver, colon, and prostate but is rare in normal tissues overall; nevertheless, it is expressed in various types of malignant tissues including lung cancer, 7 colorectal cancer, 8 prostatic cancer, 9 renal cell carcinoma, 10 breast cancer, 11 endometrial cancer, 12 ovarian cancer, 13 gestational trophoblastic neoplasia, 14 and cervical cancer. [15][16][17][18] B7-H3 is expressed in tumor cells (TCs) and stromal cells including tumor-associated vascular endothelial cells, fibroblasts, and immune cells. 7,19,20 Generally, B7-H3 is associated with tumor aggressiveness, unfavorable clinicopathological features, and poor outcomes.…”

PD‐L1 expression and immune stromal features in HPV‐independent cervical adenocarcinoma

“…[8][9][10][11] Only one study reported the expression of PD-L1 (clone E1L3N) in 50 patients with CCC of the uterine cervix, and found a positive PD-L1 expression in 22% (CPS ≥1) of tumours. 13 Only Rivera-Colon et al evaluated PD-L1 expression using PD-L1 IHC 22C3 pharmDx; PD-L1 expression was observed in 68% cases [HPVA = 87 and HPVindependent = two (PD-L1 expression was positive based on both CPS and TPS)] based on the CPS and in 29% cases based on the TPS. 11 The discrepancy between the results of these investigations can be explained by different study designs, histopathological types and different clones used.…”

“…12 There is only one report regarding the expression of PD-L1 in clear cell carcinoma (CCC) of the uterine cervix. 13 One study, including 127 patients with HPVA CA, showed that PD-L1 expression correlated with tumour-infiltrating lymphocytes (TILs). 14 The immune microenvironment and PD-L1 expression in HPV-independent CA are not completely understood.…”