Tumor Derived Extracellular Vesicles Drive T Cell Exhaustion in Tumor Microenvironment through Sphingosine Mediated Signaling and Impacting Immunotherapy Outcomes in Ovarian Cancer. Issue 14 (15th March 2022)

• Record Type: Journal Article
• Authors: Gupta, Prachi; Kadamberi, Ishaque Pulikkal; Mittal, Sonam; Tsaih, Shirng‐Wern; George, Jasmine; Kumar, Sudhir; Vijayan, Dileep K.; Geethadevi, Anjali; Parashar, Deepak; Topchyan, Paytsar; McAlarnen, Lindsey; Volkman, Brian F; Cui, Weiguo; Zhang, Kam Y. J.; Di Vizio, Dolores; Chaluvally‐Raghavan, Pradeep; Pradeep, Sunila
• Is Part Of: Advanced science. Volume 9:Issue 14(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-03-15
• Subjects: extracellular vesicles -- immunotherapy -- ovarian cancer -- S1P -- SPHK1 -- T cell exhaustion; Science -- Periodicals; 505
• DOI: 10.1002/advs.202104452
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: SPHK1 (sphingosine kinase‐1) catalyzes the phosphorylation of sphingosine to sphingosine‐1‐phosphate (S1P), is found to be highly expressed in solid tumors. Here, extracellular vesicles (EVs) are identified as the key transporters of SPHK1 to the tumor microenvironment. Consequently, SPHK1‐packaged EVs elevate S1P levels in the tumor microenvironment, where S1P appears as an immunosuppressive agent. However, the exact mechanism of how S1P mediates its immunosuppressive effects in cancer is not understood. It is investigated that S1P can induce T cell exhaustion. S1P can also upregulate programmed death ligand‐1 (PDL‐1) expression through E2F1‐mediated transcription. Notably, an SPHK1 inhibitor PF543 improves T cell‐mediated cytotoxicity. Furthermore, combining PF543 with an anti‐PD‐1 antibody reduces tumor burden and metastasis more effectively than PF543 alone in vivo. These data demonstrate a previously unrecognized mechanism of how SPHK1‐packaged EVs contribute to the progression of ovarian cancer and thus present the potential clinical application of inhibiting SPHK1/S1P signaling to improve immune checkpoint blockage (anti‐PD‐1 antibody) therapy in ovarian cancer. Abstract : The mechanism of immunosuppression through extracellular vesicles (EVs) in ovarian cancer is identified. Sphingosine kinase‐1 (SPHK1) secreted through EVs facilitates sphingosine‐1‐phosphate (S1P) synthesis in tumor microenvironment (TME) and elevates S1P. High S1P results in immune suppression through T cell‐exhaustion by upregulating programmed death ligand‐1 (PD‐L1) expression. SPHK1 inhibition improves the efficacy of immune checkpoint blockage therapy in ovarian cancer.