Abstract
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.
Highlights
Interest in boosting the immune system to fight cancer cells was evident in the literature as early as the late nineteenth century [1]
We used the Kaplan–Meier plotter dataset from ovarian cancer patients to analyze the predictive value of GLS in ovarian cancer, and the log-rank test results indicated a negative correlation between GLS expression and overall survival (n = 1656; Figure 1A) and progression-free survival (n = 1435; Figure 1B)
By analyzing the TCGA ovarian cancer dataset generated by Gene Expression Profiling Interactive Analysis (GEPIA), a significant albeit very weak correlation was observed between high expression of GLS and upregulation of immunosuppressive genes including Programmed cell death 1 ligand (PD-L1) (CD274), PD-1 (PDCD1), PD-L2 (PDCD1LG2), cytotoxic T lymphocyte-associated antigen 4 (CTLA4), and LAG3 (Supplementary Figure S1), suggesting the potential effects of GLS
Summary
Interest in boosting the immune system to fight cancer cells was evident in the literature as early as the late nineteenth century [1]. Five key immunotherapy modalities have become cutting-edge cancer treatments after undergoing extensive research and clinical trials [2]. The immune checkpoint inhibitors function to block immune checkpoint receptors, thereby reactivating tumor-infiltrating lymphocytes to perform tumor elimination functions. Immune checkpoint inhibitors, including monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death 1 (PD1), or PD1 ligand (PD-L1), are effective in the treatment of various types of cancer, especially melanoma and lung cancer [1]. There has been no approved immune checkpoint blockade therapy proposed to date, even though promising results were reported in initial trials.
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