Spatial Heterogeneity of Infiltrating T Cells in High-Grade Serous Ovarian Cancer Revealed by Multi-Omics Analysis

2021 ◽  
Author(s):  
Bin Yang ◽  
Xiong Li ◽  
Wei Zhang ◽  
Junpeng Fan ◽  
Yong Zhou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Spatial Heterogeneity ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Omics Analysis

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

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.

Neoadjuvant Chemotherapy Modulates the Tumor Microenvironment in High-Grade Serous Ovarian Cancer

2021 ◽  
Author(s):  
Zhongling Zhuo ◽  
Min Tang ◽  
Hexin Li ◽  
Lili Zhang ◽  
Bingqing Han ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
T Cells ◽  
Survival Analysis ◽  
Tumor Microenvironment ◽  
Neoadjuvant Chemotherapy ◽  
Mapk Pathway ◽  
Treatment Options ◽  
High Grade ◽  
Serous Ovarian Cancer

Abstract Background While surgical reduction with adjuvant chemotherapy is the traditional treatment for high-grade serous ovarian cancer (HGSOC), neoadjuvant chemotherapy (NACT) has increasingly been applied. This work aims to investigate the expression profiles before and after NACT, explore changes in the tumor microenvironment, expand current treatments, and design a combination of treatment options for patients. Methods We downloaded 326 pre-NACT RNA sequencing data and 37 matched pre- and post-NACT samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differentially expressed genes (DEGs) were determined with EdgeR, and Gene Ontology analysis was performed to identify the clusters responsible for the biological processes and pathways of HGSOC. Immune infiltration was analyzed using Single-sample Gene Set Enrichment Analysis (ssGSEA) and CIBERSORT. Kaplan-Meier (KM) survival analysis was performed to assess prognosis, and the potential correlations between modules and phenotypes were explored using weighted gene co-expression network analysis (WGCNA). Results After NACT, a total of 352 genes showed significant changes in RNA expression, among which 180 genes were up-regulated and 172 down-regulated. The most influential pathway was the positive regulation of mitogen-activated protein kinase (MAPK) cascade. Correlation analysis and KM survival analysis showed that overexpression of MAPK cascade genes correlated with shorter survival time in HGSOC patients. ssGSEA results showed that the expressions of anti-tumor cells (central memory CD4+ T cell and central memory CD8+ T cell) and pro-tumor cells (neutrophil and dendritic cells) were significantly increased after NACT. CIBERSORT showed that the abundances of memory B cells, NK cells, and monocytes were increased and the abundance of plasma cells was decreased after NACT. WGCNA and KM survival analysis showed that a lower abundance of Regulatory T cells (Tregs) was correlated with a better prognosis. Conclusions Gene expression of the MAPK pathway is up-regulated and the abundance of CD4+ T regulation cell decreases after NACT. Thus, the MAPK pathway may promote the differentiation of CD4+ T cells into Th17 cells while inhibiting Tregs development. The inhibited Tregs' development can lead to a better prognosis. Therefore, it is speculated that Tregs inhibitors combined with platinum-based NACT are potential treatment options for HGSOC.

A high-depth multi-omics analysis of clinically defined subsets of high-grade serous ovarian cancer

2020 ◽  
Vol 159 ◽  
pp. 77
Author(s):  
S. Lee ◽  
L. Zhao ◽  
C. Rojas ◽  
N.W. Bateman ◽  
H. Yao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Omics Analysis ◽  
High Depth

scholarly journals CXCL13 shapes immunoactive tumor microenvironment and enhances the efficacy of PD-1 checkpoint blockade in high-grade serous ovarian cancer

2021 ◽  
Vol 9 (1) ◽  
pp. e001136
Author(s):  
Moran Yang ◽  
Jiaqi Lu ◽  
Guodong Zhang ◽  
Yiying Wang ◽  
Mengdi He ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
B Cells ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Ex Vivo ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
High Grade ◽  
Serous Ovarian Cancer

BackgroundMost patients with high-grade serous ovarian cancer (HGSC) lack an effective response to immune checkpoint blockade, highlighting the need for more knowledge about what is required for successful treatment. As follicular cytotoxic CXCR5+CD8+ T cells are maintained by reinvigoration by immune checkpoint blockade in tumors, we attempted to reveal the relationship between CXCR5+CD8+ T cells and the tumor microenvironment to predict immunotherapy responses in HGSC.Methods264 patients with HGSC from two cohorts and 340 HGSC cases from The Cancer Genome Atlas cohort were enrolled. Ex vivo and in vivo studies were conducted with human HGSC tumors and murine tumor models. The spatial correlation between CXC-chemokine ligand 13 (CXCL13), CXCR5, CD8, and CD20 was evaluated by immunohistochemistry and immunofluorescence. Survival was compared between different subsets of patients using Kaplan-Meier analysis. The therapeutic effect of CXCL13 and programmed cell death-1 (PD-1) blockade was validated using human HGSC tumors and murine models.ResultsHigh CXCL13 expression was associated with prolonged survival. Tumors with high CXCL13 expression exhibited increased infiltration of activated and CXCR5-expressing CD8+ T cells. Incubation with CXCL13 facilitated expansion and activation of CXCR5+CD8+ T cells ex vivo. CXCR5+CD8+ T cells appeared in closer proximity to CXCL13 in tumors and chemotaxis towards CXCL13 in vitro. The combination of CXCL13, CXCR5, and CD8+ T cells was an independent predictor for survival. In addition, CXCL13 was associated with clusters of CD20+ B cells. CD20+ B cells predicted better patient survival in the presence of CXCL13. Histological evaluation highlighted colocalization of CXCL13 with tertiary lymphoid structures (TLSs). TLSs carried prognostic benefit only in the presence of CXCL13. CXCL13 in combination with anti-PD-1 therapy retarded tumor growth in a CD8+ T-cell-dependent manner, resulting in increased infiltration of cytotoxic CD8+ T cells and CXCR5+CD8+ T cells.ConclusionsThese data define a critical role of CXCL13 in shaping antitumor microenvironment by facilitating the maintenance of CXCR5+CD8+ T cells in TLSs and support a clinical investigation for a combination of CXCL13 and PD-1 blockade therapy in HGSC.

Profound elevation of CD8+ T cells expressing the intraepithelial lymphocyte marker CD103 (αE/β7 Integrin) in high-grade serous ovarian cancer

2010 ◽  
Vol 118 (3) ◽  
pp. 228-236 ◽  
Author(s):  
John R. Webb ◽  
Darin A. Wick ◽  
Julie S. Nielsen ◽  
Eric Tran ◽  
Katy Milne ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Cd8 T Cells ◽  
Intraepithelial Lymphocyte ◽  
High Grade ◽  
Serous Ovarian Cancer

scholarly journals 431 First-in-human phase I clinical trial evaluating intraperitoneal administration of MOv19-BBz CAR T cells in patients with alpha folate receptor-expressing recurrent high grade serous ovarian cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A461-A461
Author(s):  
Payal Shah ◽  
Richard Shlanksy-Goldberg ◽  
Lainie Martin ◽  
Gregory Nadolski ◽  
Elizabeth Hexner ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
Folate Receptor ◽  
Intraperitoneal Administration ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Car T Cells ◽  
Car T ◽  
Signaling Domains

BackgroundMost women with epithelial ovarian cancer develop uniformly incurable disease recurrence. Chimeric antigen receptor (CAR) T cells pair the MHC-independent tumor-recognition capabilities of monoclonal antibodies with the cytotoxicity of effector T cells. The success of CAR T cell therapy in solid tumors has been hindered by (1) difficulty identifying highly expressed, tumor-specific, cell surface target antigens; (2) limited trafficking and infiltration; and (3) suboptimal cytotoxic activity. Alpha folate receptor (FRα) is a transmembrane protein involved in cellular folate transport; expression has been reported in 80% of ovarian cancer, with limited physiologic expression on epithelial cells including bronchial, renal, and intestinal tissue. We hypothesize that intraperitoneal administration of alpha folate receptor (FRα) directed CAR T cells with dual 4-1BB and TCRzeta signaling domains will circumvent the above challenges and be safe, feasible, and elicit anti-tumor responses.MethodsWe initiated a first-in-human phase I clinical trial to evaluate the feasibility, safety and preliminary efficacy of intraperitoneal administration of FRα directed CAR T cells with and without antecedent lymphodepleting chemotherapy (LDC) in women with recurrent high grade serous ovarian cancer. The lentivirally-transduced CAR is composed of a MOv19 anti-FRα-specific single chain variable fragment fused to 4-1BB and TCRzeta signaling domains. Eligible patients have persistent or recurrent high grade serous epithelial ovarian, fallopian tube, or primary peritoneal carcinoma that is not platinum refractory and expresses ≥2+ FRα staining in ≥70% of tumor cells. Subjects must have an ECOG performance status 0–1, measurable disease, adequate hematologic and organ function, and must have progressed on at least two prior chemotherapy regimens for advanced disease. Patients undergo biopsy pre-infusion and Day +14 after infusion. After same-day placement of an intraperitoneal catheter by Interventional Radiology, CAR T cells are administered via a single infusion on three dose cohorts: Cohort 1 (starting cohort), 1–3x107/m2 cells without LDC; Cohort 2, 1–3x107/m2 CAR T cells after LDC; Cohort 3, 1–3x108/m2 cells after LDC. Catheter is removed after infusion. A 3+3 dose escalation design to determine maximum tolerated dose (MTD) yields approximately 9 to 18 subjects. The primary objective is safety and feasibility, and secondary objectives are anti-tumor response (endpoints: overall response rate based on RECIST v 1.1 and irRECIST when feasible, progression-free survival and overall survival). Correlative endpoints include CAR T cell engraftment and persistence in peripheral blood and body fluids examined via quantitative PCR of CAR T DNA, and bioactivity of CAR T cells. Enrollment is ongoing.Trial RegistrationThis trial is registered at ClinicalTrials.gov (NCT03585764).Ethics ApprovalThis study was approved by the Institutional Review Board at the University of Pennsylvania (IRB 830111). All subjects provided written informed consent prior to any study-related procedures.

Sign in / Sign up

Export Citation Format

Share Document