Abstract 4884: Reversing immune desertification for effective cancer therapy

Abstract Patients with tumors that have a “cold, or “immune desert” phenotype typically have poor outcomes on immune checkpoint therapy (ICT). Aberrant sphingosine-1-phosphate (S1P) signaling in tumors and in their draining lymph nodes (TDLN) appears to causes a common form of immune desertification by disabling or stalling lymphocyte egress from the TDLN, ultimately restricting immune trafficking to tumors. Clinically, tumor expression levels of the S1P producing enzyme sphingosine kinase 1 (SPHK1) strongly and negatively correlate with survival of patients after immune checkpoint inhibitor (ICI) therapy) and pre-clinically correlate with reduced tumor infiltrating lymphocytes (TILs). While there are five known S1P receptors (S1PR1-5), the expression of S1PR1 is required for lymphocyte egress from lymphatic organs. Abnormal S1P signaling or S1PR1 agonists functionally downregulate S1PR1 levels, trapping lymphocytes in the lymph node and is the mechanism of action of certain immunosuppressants (e.g., fingolimod) used to treat autoimmune diseases such as multiple sclerosis. In preliminary studies we have demonstrated in murine cancer models treated with pharmacologically optimized S1P degrading enzymes (SGPL1), that depleting extracellular S1P dramatically increases the trafficking of lymphocytes out of TDLNs, increases tumor T cell infiltration and strongly or completely inhibits tumor growth when administered as a single agent. Data from our lab suggests that deeply lowering extracellular S1P without eliminating internal stores of S1P needed for lymphatic egress is a powerful modality for increasing the level of S1PR1 on lymphocytes, releasing tumor specific T cells from TDLNs, and ultimately increasing tumor immune infiltration. Essentially the exact opposite mechanism as observed with immunosuppressants such as fingolimod. Current small molecule inhibitors of S1P production can only lower extracellular S1P levels by ∼ 50% via decreasing intracellular pools and only show limited anti-cancer activity. A cold tumor microenvironment is a common phenomenon that limits ICT efficacy and therapeutics that could enhance lymphocyte trafficking to the tumor would represent a significant advance for improving patient outcomes. Citation Format: Alessandra Araujo, Max Rodnick-Smith, Ranya Al-Khaledy, Mark Badeaux, Everett Stone. Reversing immune desertification for effective cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4884.