Tumor Derived Extracellular Vesicles Drive T Cell Exhaustion in Tumor Microenvironment through Sphingosine Mediated Signaling and Impacting Immunotherapy Outcomes in Ovarian Cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 15, 2022
- Source ID
- 10.1002/advs.202104452
Entities
People
- Anjali Geethadevi
- Brian F Volkman
- Deepak Parashar
- Dileep K. Vijayan
- Dolores Di Vizio
- Ishaque Pulikkal Kadamberi
- Jasmine George
- Kam Y J Zhang
- Lindsey Mcalarnen
- Paytsar Topchyan
- Prachi Gupta
- Pradeep Chaluvally‐raghavan
- Shirng‐wern Tsaih
- Sonam Mittal
- Sudhir Kumar
- Sunila Pradeep
- Weiguo Cui
Organizations
- Cedars-Sinai Medical Center
- Medical College of Wisconsin
- United States Department of Defense