A Combination of Glutaminase Inhibitor 968 and PD-L1 Blockade Boosts the Immune Response against Ovarian Cancer

• Published in: Biomolecules (Basel, Switzerland) Vol. 11; no. 12; p. 1749
• Main Authors: Wang, Jing-Jing, Siu, Michelle Kwan-Yee, Jiang, Yu-Xin, Leung, Thomas Ho-Yin, Chan, David Wai, Wang, Huo-Gang, Ngan, Hextan Yuen-Sheung, Chan, Karen Kar-Loen
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.11.2021; MDPI
• Subjects: Animals; Annexin V; Antibodies; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Benzophenanthridines - administration & dosage; Benzophenanthridines - pharmacology; Cancer therapies; CD3 antigen; CD4 antigen; CD8 antigen; Cell culture; Cell death; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemokines; Clinical outcomes; CXCL10 protein; CXCL11 protein; Drug Synergism; Female; Flow cytometry; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Glutaminase; Glutaminase - genetics; Glutamine; glutamine metabolism; Granzyme B; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - administration & dosage; Immune Checkpoint Inhibitors - pharmacology; Immune response; Immune system; Immunotherapy; Isotypes; Kidneys; Lung cancer; Lymphocytes; Lymphocytes T; Medical prognosis; Metabolism; Metastases; Mice; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; PD-L1 protein; T cells; Treatment Outcome; Tumor cells; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays; Xenografts; Hong Kong China; Canada; United States > US; glutamine metabolism; T cells; ovarian cancer; immunotherapy
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom11121749

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.