Blockading programmed death ligand 1 (PD-L1) shows promising results in patients with some cancers, but not in those with ovarian cancer. V-domain Ig suppressor of T cell activation (VISTA) is a recently discovered immune checkpoint protein that suppresses T cell activation. This study aimed to investigate the expression and clinical significance of VISTA in ovarian cancer as well as its relationship with PD-L1. VISTA and PD-L1 levels in 146 ovarian cancer samples were assessed using immunohistochemistry. We investigated the association between VISTA and other clinicopathological variables, including survival. The associations between the VISTA-encoding C10orf54 gene, other immune checkpoints, and survival were analyzed. VISTA was detected in 51.4% of all samples and 46.6% of PD-L1-negative samples; it was expressed in 28.8%, 35.6%, and 4.1% of tumor cells (TCs), immune cells (ICs), and endothelial cells, respectively. Furthermore, VISTA expression was associated with pathologic type and PD-L1 expression. Moreover, VISTA expression in TCs, but not in ICs, was associated with prolonged progression-free and overall survival in patients with high-grade serous ovarian cancer. The expression of C10orf54 mRNA was associated with prolonged overall survival and immune escape-modulating genes. These results showed that VISTA expression in ovarian tumor cells was associated with a favorable prognosis in patients with high-grade serous ovarian cancer; however, additional studies are required to better understand the expression and role of VISTA in ovarian cancer. Keywords Ovarian cancer • PD-L1 • VISTA • Immune checkpoints • Prognosis Abbreviations CTLA4 Cytotoxic T-lymphocyte-associated protein 4 FIGO International federation of gynecology and obstetrics HGSOC High-grade serous ovarian carcinoma IC Immune cell LAG3 Lymphocyte activation gene-3 TCGA The cancer genome atlas TC Tumor cell TIGIT T cell immunoreceptor with Ig and ITIM domains TIM-3 T cell immunoglobulin and mucin domain-3 TMA Tumor tissue microarray VISTA V-domain Ig suppressor of T cell activation Electronic supplementary material The online version of this article (

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Background: Epithelioid trophoblastic tumors (ETTs) are the rarest type of gestational trophoblastic neoplasias. We investigated the clinical features, treatments, outcomes, and prognostic factors in patients with ETT, and explored potential therapeutic targets.Methods: We retrospectively analyzed the clinical features, treatments, survival, and prognostic factors of 21 ETT patients treated at our institution between January 2002 and December 2017. Expression levels of programmed cell death 1 (PD-1), PD-1 ligands (PD-L1and PD-L2), B7 family ligands (B7-H3, B7-H4, V-domain Ig suppressor of T cell activation [VISTA], and B7-H6), and CD105 expression were assessed by immunohistochemistry.Results: Fourteen patients with ETT (66.7%) presented with irregular vaginal bleeding. Three stage I patients (14.3%) with normal β-human chorionic gonadotropin (β- hCG) levels underwent hysterectomy alone. Of the remaining 18 patients who had elevated β-hCG levels (85.7%), 1 received chemotherapy and 17 underwent surgery and multi-agent chemotherapy. After treatment, 17 patients (81.0%) achieved complete remission (2 of whom [11.8%] later relapsed) and 4 (19.0%) with stage IV died of their disease. On univariate and multivariate analyses, stage IV disease was an independent prognostic factor for overall and disease-free survival (P < 0.001). PD-L1, B7-H3, and CD105 were detected in 100% of samples, PD-L2 and VISTA in 82%, B7-H6 in 18%, and B7-H4 was undetectable in ETT cells.Conclusions: Hysterectomy and metastatic lesion resection are essential for controlling ETT. Surgery plus chemotherapy are recommended for patients with abnormal β-hCG levels and metastatic disease. PD-L1, PD-L2, B7-H3, VISTA and CD105 are potential therapeutic targets for metastatic ETT.

Aims: The B7 family check-point molecules are potential therapeutic targets in cancer immunotherapy. However, their expression status in human gestational trophoblastic neoplasia (GTN) remains unknown. We investigated the expression profiles of the B7 family check-point proteins PD-L1, PD-L2, B7-H3, B7-H4, VISTA and B7-H6 in GTN and their clinical significance. Methods and results: We identified 112 patients with GTN, including 68 with choriocarcinoma, 33 with placental-site trophoblastic tumour (PSTT) and 11 with epithelioid trophoblastic tumour (ETT). Immunohistochemical staining was performed on whole-tissue GTN sections using anti-B7 family antibodies. VISTA expression was immunohistochemically analysed using microarrays of normal human tissues and of 20 common cancers. PD-L1 and B7-H3 were highly expressed in all GTN tumours, while PD-L2 was expressed in 87.5% of the samples. B7-H4 and B7-H6 were negative in 100% and 98.2% of the samples, respectively. PD-L1, B7-H3 and VISTA levels were significantly higher in choriocarcinomas and PSTTs than in ETTs. There was no association between B7 family check-point expression in tumour cells and disease stage, prognostic score or patient outcomes (complete remission versus death). VISTA protein was widely overexpressed in 98.2% of all the GTN, but its expression varied in other cancer types and was negative in normal adult and fetal tissues except placental trophoblasts and splenic lymphocytes. Conclusions: The GTN trophoblast cells show high expression of PD-L1, B7-H3 and VISTA in a manner that is independent of clinical outcomes. These proteins may be potential immunotherapeutic targets when treating GTN. Thymus (0/3) Colon (0/3) Sternum (0/2) Myocardium (0/5) Spleen (0/5) Lung (0/5) Aorta (0/3) Diaphragm (0/3) Skin (0/5) Kidney (0/4) Ovary (0/1) Hippocampus (0/4) Adrenal (0/5) Bladder (0/3) Stomach (0/5) Small intestine (0/4) Oesophagus (0/2) Testis (0/2) Pancreas (0/5) Liver (0/5) Brain (0/5) Adult organs (number positive/total cores) Oesophagus (0/8) Tongue (0/3) Thyroid (0/14) Small intestine (0/11) Spleen (2/2) Brain (0/6) Bladder (0/4) Skeletal muscle (0/7) Prostate (0/3) Skin (0/3) Colon (0/11) Myocardium (0/3) Lung (0/16) Trachea (0/3) Pancreas (0/8) Seminal vesicle (0/1) Appendix (0/5) Rectum (0/8) Breast (0/5) Uterine cervix (0/10) Testis (0/7) Aorta (0/3) Liver (0/8) Placenta (28/28) Larynx (0/3) Penis (0/5) Uterus (0/4) Stomach (0/14) Kidney (0/5) Cancer samples (number positive/total cores) Brain (0/6) Larynx (1/3) Stomach (0/6) Ureter (1/5) Rectum (0/5) Breast (0/5) Penis (3/5) Thyroid (1/10) Uterus (0/8) Ovary (2/6) Kidney (0/10) Pancreas (0/5) Prostate (0/6) Colon (0/5) Lung (0/7) Oesophagus (0/4) Liver (0/6) Testis (0/3) Bladder (0/6) Uterine cervix (2/8)

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PurposeThe incidence of cervical cancer in young women is increasing. This study aimed to analyze the clinicopathological characteristics, treatment, and prognoses of women aged ≤25 years with cervical cancer.Patients and methodsMedical record data of 60 cervical cancer patients aged ≤25 years treated at Peking Union Medical College Hospital between January 1986 and December 2017 were reviewed. The overall survival rate was estimated using the Kaplan–Meier method. Prognosis-related risk factors were analyzed using univariate and multivariate analyses.ResultsAmong the 60 patients, 44 (73.3%) were diagnosed with cervical carcinoma and 16 (26.7%) with cervical sarcoma. In the cervical carcinoma group, the most common histology was squamous cell carcinoma (n=22, 50.0%) followed by adenocarcinoma (n=18, 40.9%). Notably, clear cell carcinoma dominated cervical adenocarcinomas at 61.1% (11/18). In the cervical sarcoma group, embryonal rhabdomyosarcoma comprised 50% of the cases (8/16). A total of eleven patients with cervical carcinoma underwent fertility-sparing surgeries, and the live birth rate approached 66.7%. The estimated 5-year overall survival rate of the entire cohort was 79.8% with no statistically significant difference between the carcinoma and sarcoma groups (74.3% vs 93.3%, P=0.14). Stage (RR 6.71, 95% CI 1.366–32.970, P=0.019) and lymph node metastasis (RR 9.09, 95% CI 1.050–78.732, P=0.045) were independent risk factors for poor prognosis in those young patients with cervical carcinoma.ConclusionAdenocarcinoma and sarcoma of the cervix comprise the majority of cervical cancer in young women; their overall prognoses are not worse than older patients; the survival rates tend to vary widely according to histologic subtypes.

B7-H3, which has been reported to be a co-regulatory ligand of the B7 family, can suppress T cell-mediated immunity and has also been reported to be expressed in many malignancies. In this study, we found that B7-H3 was primarily expressed in the cytoplasm of cervical cancer cells and was associated with deep stromal invasion (P=0.0013). The disease-free survival data showed that cervical cancer patients whose tumours were positive for B7-H3 expression had higher mortality rates compared with patients whose tumours lacked B7-H3 expression (P=0.0317), representing an advantage over P16 (P=0.3486). In contrast, the level of serum B7-H3 was low in cases of cervical intraepithelial neoplasia and cervical cancer. The silencing of B7-H3 in the SiHa, CaSki and H8 cell lines inhibited cell proliferation and enhanced apoptosis, while the over-expression of B7-H3 in HeLa cells showed inverse changes. These changes were partially due to the regulation of cell cycle- and apoptosis-related proteins, such as E2F, P21, P16, PARP-1, Caspase-8, Bax, Bcl-2 and Bcl-xl. The results of in vivo experiments revealed that the knockdown of B7-H3 in tumour cells suppressed SiHa cell growth in nude mice. Overall, B7-H3 is involved in the development and progression of cervical intraepithelial neoplasia and cervical cancer through its effects on the cell cycle and apoptosis, which are mediated via the E7/Rb pathway. B7-H3 also has the potential to be a useful prognostic marker for patients with cervical cancer.