Therapeutic administration of an engineered sphingosine-1-phosphate lyase improves T cell trafficking to tumors and enhances antitumor response 2160

Abstract Description Immunotherapy has revolutionized cancer treatment; however, only limited aspects of the tumor-immune interaction have been exploited successfully. While it is well-known that trafficking of T cells is often impaired during cancer, there are no available therapies that address this aspect of antitumor immunity. Clinically, expression levels of the sphingosine-1-phosphate producing enzyme sphingosine kinase 1 negatively correlates with survival of melanoma patients after immune checkpoint inhibitor (ICI) therapy. We therefore hypothesized that aberrant S1P signaling in tumors causes immune exclusion by impeding lymphocyte egress from the tumor draining lymph node (TDLN). We tested the efficacy of an engineered S1P-degrading enzyme (S1PL) on established murine tumors and performed immune profiling of TDLN and intratumoral T cell populations. S1PL increased both trafficking of lymphocytes out of TDLNs and T cell infiltration of tumors. Mice treated with S1PL evinced a higher proportion of S1P1+ circulating T cells relative to controls, suggesting that liberation of T cells from the TDLN occurred through the S1P/S1P1 axis. Increased lymphocyte trafficking correlated with strong inhibition of tumor growth and enhanced efficacy of ICI therapy. Administration of S1PL may be an attractive strategy for improving therapies that rely on antitumor adaptive immunity. This approach may thus be potent in settings wherein tumor-mediated immune exclusion is a dominant method of immune escape. Funding Sources Texas Biologics & CPRIT RP240454 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)