Gene expression profiling of CD8+
 T cells induced by ovarian cancer cells suggests a possible mechanism for CD8+
 Treg cell production

Programmed cell death 1 ligand (PD-L1) blockade has been used therapeutically in the treatment of ovarian cancer, and potential combination treatment approaches are under investigation to improve the treatment response rate. The increased dependence on glutamine is widely observed in various type of tumors, including ovarian cancer. Kidney-type glutaminase (GLS), as one of the isotypes of glutaminase, is found to promote tumorigenesis. Here, we have demonstrated that the combined treatment with GLS inhibitor 968 and PD-L1 blockade enhances the immune response against ovarian cancer. Survival analysis using the Kaplan–Meier plotter dataset from ovarian cancer patients revealed that the expression level of GLS predicts poor survival and correlates with the immunosuppressive microenvironment of ovarian cancer. 968 inhibits the proliferation of ovarian cancer cells and enhances granzyme B secretion by CD8+ T cells as detected by XTT assay and flow cytometry, respectively. Furthermore, 968 enhances the apoptosis-inducing ability of CD8+ T cells toward cancer cells and improves the treatment effect of anti-PD-L1 in treating ovarian cancer as assessed by Annexin V apoptosis assay. In vivo studies demonstrated the prolonged overall survival upon combined treatment of 968 with anti-PD-L1 accompanied by increased granzyme B secretion by CD4+ and CD8+ T cells isolated from ovarian tumor xenografts. Additionally, 968 increases the infiltration of CD3+ T cells into tumors, possibly through enhancing the secretion of CXCL10 and CXCL11 by tumor cells. In conclusion, our findings provide a novel insight into ovarian cancer cells influence the immune system in the tumor microenvironment and highlight the potential clinical implication of combination of immune checkpoints with GLS inhibitor 968 in treating ovarian cancer.

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Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis

Journal of Clinical Investigation ◽

10.1172/jci59255 ◽

2011 ◽

Vol 121 (10) ◽

pp. 4170-4179 ◽

Cited By ~ 161

Author(s):

James C. Lee ◽

Paul A. Lyons ◽

Eoin F. McKinney ◽

John M. Sowerby ◽

Edward J. Carr ◽

...

Keyword(s):

Gene Expression ◽

Ulcerative Colitis ◽

T Cells ◽

Gene Expression Profiling ◽

Cd8 T Cells ◽

Crohn Disease ◽

Expression Profiling

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Gene expression profiling of CD3γ, δ, ϵ, and ζ chains in CD4+and CD8+T cells from human umbilical cord blood

Hematology ◽

10.1179/102453309x12583347113537 ◽

2010 ◽

Vol 15 (4) ◽

pp. 230-235 ◽

Cited By ~ 6

Author(s):

Shaohua Chen ◽

Lijian Yang ◽

Xiaoye Lu ◽

Bo Li ◽

John Yeuk-Hon Chan ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Cord Blood ◽

Gene Expression Profiling ◽

Umbilical Cord ◽

Cd8 T Cells ◽

Umbilical Cord Blood ◽

Expression Profiling ◽

Human Umbilical Cord Blood ◽

Human Umbilical Cord

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Single-cell gene-expression profiling reveals qualitatively distinct CD8 T cells elicited by different gene-based vaccines

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1013084108 ◽

2011 ◽

Vol 108 (14) ◽

pp. 5724-5729 ◽

Cited By ~ 68

Author(s):

L. Flatz ◽

R. Roychoudhuri ◽

M. Honda ◽

A. Filali-Mouhim ◽

J.-P. Goulet ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Single Cell ◽

Gene Expression Profiling ◽

Cd8 T Cells ◽

Expression Profiling ◽

Cell Gene Expression ◽

Cell Gene

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1-MT inhibits the invasion of CBP-resistant ovarian cancer cells via down-regulating IDO expression and re-activating immune cells function

BMC Pharmacology and Toxicology ◽

10.1186/s40360-020-00439-w ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Huihan Ma ◽

Qian Qin ◽

Jiaqing Mi ◽

Qinmei Feng

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

Nk Cells ◽

Cancer Cells ◽

Cell Line ◽

Cd8 T Cells ◽

Ovarian Cancer Cells ◽

Skov3 Cell ◽

Conceptual Foundation ◽

Tumor Immune Escape

Abstract Background The indoleamine 2, 3-dioxygenase (IDO) inhibitor 1-methyl-tryptophan (1-MT) is currently being used in clinical trials in patients with relapsed or refractory solid tumors by inhibiting tumor immune escape. A greater understanding of IDO activity is required to begin to understand the molecular mechanism by which drugs work. This study was conducted to investigate of the clinical significance of 1-methyl-tryptophan (1-MT) in treating carboplatin-resistant (CBP-resistant) ovarian cancer and its mechanism of action. Methods Using a medium dose, intermittent treatment method, a clinically relevant CBP-resistant human ovarian cancer cell line (SKOV3/CBP) was established. SKOV3/CBP cells were treated with normal serum (control) or 1-MT (0.25 ng/mL) for 4 h (SKOV3/CBP + 1-MT). Cell proliferation, invasion and IDO expression in SKOV3, SKOV3/CBP and SKOV3/CBP + 1-MT cells were determined by MTT assays, Matrigel invasion chambers assays and ELISAs, respectively. The half-maximal inhibitory concentration (IC50) and resistance index (RI) were also calculated. The killing ability of the NK cells and CD8+ T cells co-cultured with SKOV3, SKOV3/CBP and SKOV3/CBP + 1-MT cells were determined by LDH activity assays and the INF-γcounting method. Results The SKOV3/CBP cell line displayed an increased IC50 compared to the SKOV3 cell line (P < 0.05) under CBP treatment. Treatment with 1-MT significantly decreased the IC50 and RI of SKOV3/CBP cells. Furthermore, 1-MT treatment not only reduced the invasion ability, but also suppressed IDO expression in the drug-resistant SKOV3/CBP + 1-MT cell line as compared to the SKOV3/CBP cell line. Furthermore, 1-MT enhanced the killing ability of NK cells and the amount of INF-γsecreted from CD8+ T cells which were co-cultured with the SKOV3/CBP cell line. Conclusion Our data suggested that 1-MT inhibits the invasion of CBP-resistant ovarian cancer cells via down-regulation of IDO expression which leads to re-activation of immune cell function. We provide a conceptual foundation for the clinical development of 1-MT as an anti-tumor immunomodulator for chemotherapy resistant ovarian cancer patients.

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