Sphingosine-Mediated Immune Suppressive Effects in Ovarian Cancer
Abstract
Rationale: Immunotherapy, like immune checkpoint inhibitors against PD-L1 and PD-1, has revolutionized cancer therapy. In contrast to other malignancies such as melanoma or renal cell cancer, immunotherapy has not been approved for ovarian cancer treatment. Despite the increasing availability of treatment approaches that target tumor immune surveillance in ovarian carcinoma, selecting patient groups that particularly benefit from these treatment modalities is clinically challenging as predictive biomarkers are lacking. The reason for the low response to immunotherapy in ovarian cancer remains unknown, which is a critical gap in our knowledge. Therefore, there is an immense need to delineate the mechanisms that abrogate or inhibit the actions of immunotherapy in ovarian cancer. We found an elevated level of Sphingosine-1-phosphate (S1P) in the blood plasma of ovarian cancer patients and high expression of sphingosine kinase-1 (SPHK1) enzyme in ovarian cancer tissue samples. As a consequence, we found that S1P causes immune suppression in ovarian cancer by inhibiting the actions of helper-T cells and cytotoxic T cells. While our data showed that SPHK1 mRNA is highly produced by the tumor cells, we found that SPHK1 is highly expressed in the tumor microenvironment than in the tumor cells. Based on our data, we hypothesize that S1P signaling acts as a crucial autocrine loop for the upregulation of PDL1 in tumor cells for immune-suppressed tumor microenvironment. Our central hypothesis in this proposal is that tumor cells employ exosomes to deliver SPHK1 to the tumor microenvironment for the production of S1P in the tumor microenvironment. Ovarian Cancer Advocacy Plans: A highly experienced ovarian cancer advocate, Ms. Sachia Powell, will participate as the ovarian cancer advocate in this research. Ms. Powell is an active participant and team captain in the Rivkin center SummeRun. Ms. Powell will bring the approaches she has used successfully in ovarian cancer advocacy to this grant. She will provide the patient perspective when research projects are designed and implemented and has been involved in all phases of the development of this proposal. Ms. Powell will be actively involved in all aspects of the proposed research program, including planning and oversight, program evaluation, and/or dissemination of information to the public through her advocacy programs. Expected Outcome: Our team, with complementary expertise in the proposed approaches, reveal a novel mechanism by which S1P/SPHK1 suppresses the immune system in primary and metastatic ovarian cancer. This project will establish a novel mechanism for S1P/SPHK1 in the immune suppression of primary and metastatic ovarian cancer. The scientific question and the proposed research are significant because we expect the completion of our studies to determine whether S1P, S1PR1, and/or SPHK1 could be used as biomarkers to predict outcomes of immunotherapy. Apart from that, inhibiting SPHK1 will provide an unprecedented opportunity to synergize sensitize PD-1 blockade in treating ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110413
Entities
People
- Sunila Pradeep
Organizations
- Medical College of Wisconsin
- United States Army