scholarly journals VISTA expression is associated with a favorable prognosis in patients with high-grade serous ovarian cancer

2019 ◽  
Vol 69 (1) ◽  
pp. 33-42 ◽  
Author(s):  
Liju Zong ◽  
Yuncan Zhou ◽  
Ming Zhang ◽  
Jie Chen ◽  
Yang Xiang
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
T Cell ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Checkpoints ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Favorable Prognosis

AbstractBlockading 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.

scholarly journals PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emily Lee ◽  
Sarah Szvetecz ◽  
Ryan Polli ◽  
Angelo Grauel ◽  
Jayson Chen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Standard Of Care ◽  
Tumor Growth Inhibition ◽  
High Grade ◽  
Ovarian Cancers ◽  
Late Stage Diagnosis ◽  
Anti Tumor Activity

AbstractHigh-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

scholarly journals Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach

2021 ◽  
Vol 22 (8) ◽  
pp. 4109
Author(s):  
Mankgopo M. Kgatle ◽  
Tebatso M. G. Boshomane ◽  
Ismaheel O. Lawal ◽  
Kgomotso M. G. Mokoala ◽  
Neo P. Mokgoro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Cancer Control ◽  
Lymphocyte Activation ◽  
Immune Checkpoints ◽  
Mortality And Morbidity ◽  
Domain 3

Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.

scholarly journals Distinct T cell receptor repertoire diversity of clinically defined high-grade serous ovarian cancer treatment subgroups

iScience ◽  
2021 ◽  
Vol 24 (2) ◽  
pp. 102053
Author(s):  
Sanghoon Lee ◽  
Li Zhao ◽  
Latasha D. Little ◽  
Shannon N. Westin ◽  
Amir A. Jazarei ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Receptor Repertoire ◽  
Repertoire Diversity ◽  
T Cell Receptor Repertoire ◽  
Cell Receptor Repertoire

PAX8 lineage-driven T cell-engaging antibody for the treatment of high-grade serous ovarian cancer

2021 ◽  
Author(s):  
Emily Lee ◽  
Andrew Anh Nguyen ◽  
Sarah Szvetecz ◽  
Ryan Polli ◽  
Angelo Grauel ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Standard Of Care ◽  
Tumor Growth Inhibition ◽  
High Grade ◽  
Ovarian Cancers ◽  
Late Stage Diagnosis ◽  
Anti Tumor Activity

Abstract High-grade serous ovarian cancers (HGSOC) represent the most common of the ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell-engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 Fabs with the anti-CD3 SP34 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mpk. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles supportive of consideration for treatment of high-grade serous ovarian cancers.

scholarly journals KLF7: a new candidate biomarker and therapeutic target for high-grade serous ovarian cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Marta De Donato ◽  
Gabriele Babini ◽  
Simona Mozzetti ◽  
Marianna Buttarelli ◽  
Alessandra Ciucci ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Prognostic Marker ◽  
Late Stage ◽  
Therapeutic Target ◽  
Family Members ◽  
High Grade ◽  
Serous Ovarian Cancer

Abstract Background In spite of great progress in the surgical and clinical management, until now no significant improvement in overall survival of High-Grade Serous Ovarian Cancer (HGSOC) patients has been achieved. Important aspects for disease control remain unresolved, including unclear pathogenesis, high heterogeneity and relapse resistance after chemotherapy. Therefore, further research on molecular mechanisms involved in cancer progression are needed to find new targets for disease management. The Krüppel-like factors (KLFs) are a family of transcriptional regulators controlling several basic cellular processes, including proliferation, differentiation and migration. They have been shown to play a role in various cancer-relevant processes, in a context-dependent way. Methods To investigate a possible role of KLF family members as prognostic biomarkers, we carried out a bioinformatic meta-analysis of ovarian transcriptome datasets in different cohorts of late-stage HGSOC patients. In vitro cellular models of HGSOC were used for functional studies exploring the role of KLF7 in disease development and progression. Finally, molecular modelling and virtual screening were performed to identify putative KLF7 inhibitors. Results Bioinformatic analysis highlighted KLF7 as the most significant prognostic gene, among the 17 family members. Univariate and multivariate analyses identified KLF7 as an unfavourable prognostic marker for overall survival in late-stage TCGA-OV and GSE26712 HGSOC cohorts. Functional in vitro studies demonstrated that KLF7 can play a role as oncogene, driving tumour growth and dissemination. Mechanistic targets of KLF7 included genes involved in epithelial to mesenchymal transition, and in maintaining pluripotency and self-renewal characteristics of cancer stem cells. Finally, in silico analysis provided reliable information for drug-target interaction prediction. Conclusions Results from the present study provide the first evidence for an oncogenic role of KLF7 in HGSOC, suggesting it as a promising prognostic marker and therapeutic target.

Combined Immunoscore of CD103 and CD3 Identifies Long-Term Survivors in High-Grade Serous Ovarian Cancer

2016 ◽  
Vol 26 (4) ◽  
pp. 671-679 ◽  
Author(s):  
Hans-Christian Bösmüller ◽  
Philipp Wagner ◽  
Janet Kerstin Peper ◽  
Heiko Schuster ◽  
Deborah Lam Pham ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Clinical Outcome ◽  
Prognostic Value ◽  
Intraepithelial Lymphocytes ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Term Survival ◽  
Cell Counts

ObjectiveIncreased numbers of tumor-infiltrating lymphocytes (TILs) in high-grade serous ovarian cancer (HGSC) are associated with improved clinical outcome. Intraepithelial localization of TILs might be regulated by specific homing receptors, such as CD103, which is widely expressed by intraepithelial lymphocytes. Given the emerging role of CD103+ TILs, we aimed to assess their contribution to the prognostic value of immunoscoring in HGSC.MethodsThe density of intratumoral CD3+ and CD103+ lymphocytes was examined by immunohistochemistry on a tissue microarray of a series of 135 patients with advanced HGSC and correlated with CD4+, CD8+, CD56+, FoxP3+, and TCRγ+ T-cell counts, as well as E-cadherin staining and conventional prognostic parameters and clinical outcome.ResultsBoth the presence of CD103+ cells, as well as high numbers of intraepithelial CD3+ lymphocytes (CD3E), showed a significant correlation with overall survival, in the complete series, as well as in patients with optimal debulking and/or platinum sensitivity. Combining CD3 and CD103 counts improved prognostication and identified 3 major subgroups with respect to overall survival. The most pronounced effect was demonstrated for patients with optimally resected and platinum-sensitive tumors. Patients with CD3high/CD103high tumors showed a 5-year survival rate at 90%, CD3low/CD103high at 63%, and CD3low/CD103low at 0% (P < 0.001).ConclusionsThese results suggest that combined assessment of CD103 and CD3 counts improves the prognostic value of TIL counts in HGSC and might identify patients with early relapse or long-term survival based on the type and extent of the immune response.

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