Depleting S1P to reverse immune exclusion for effective cancer immunotherapy

University Of Texas At Austin, Austin TX

Investigators

Abstract

PROJECT SUMMARY The overarching goal of this research proposal is to (i) demonstrate a completely novel approach for cancer immunotherapy in which degradation of extracellular sphingosine-1-phosphate (S1P) enhances lymphocyte trafficking to and infiltration of tumors, especially those that are known to exclude and/or strongly suppress cytotoxic T cells and (ii) generate a developmental candidate therapeutic S1P degrading enzyme suitable for subsequent clinical development. Patients with tumors that have a “cold”, “immune excluded”, or “immune desert” phenotype typically have poor outcomes on immune checkpoint therapy (ICT). These immune “cold” tumors often result from impaired trafficking of lymphocytes from the sentinel lymph nodes into circulation. Extracellular S1P, a bioactive lipid arising from the tumor and/or tumor draining lymph nodes (TDLN) appears to play a significant role in blocking tumor specific T cell circulation and infiltration by stalling or sequestering lymphocytes in the TDLN, keeping T cells from entering circulation and migrating to tumors. Along these lines, elevated S1P synthesis arising from tumoral upregulation of a kinase that generates S1P, SPHK1, strongly correlates with resistance to immunotherapy and poor patient survival in multiple tumor types. In preliminary studies, we developed a prokaryotic S1P degrading enzyme tool compound (StS1PL) and demonstrated in murine cancer models that treatment with StS1PL depletes extracellular S1P, dramatically increases the accumulation of activated T cells in tumors, and strongly or completely inhibits tumor growth when administered as a single agent. We found that the anti-tumor effects of StS1PL strongly depend upon CD8+ T cells and that the CD8+ T cells found in the tumor are antigen-specific and appear highly activated. The work proposed here will test the hypothesis that the reduction of extracellular S1P is a powerful modality for releasing tumor specific T cells from TDLNs, allowing them to recirculate and enhance tumor immune surveillance. Through this work, we will determine if immune “cold” tumors can be made responsive to immunotherapy (Aim 1), and we will elucidate mechanisms by which S1P reduction facilitates T cell activation, differentiation, redistribution between tissues, and trafficking to the tumor microenvironment (Aim 2). Successful completion of these studies will yield a tractable strategy for treating tumors that are refractory to immunotherapies, as well as a more detailed understanding of the process by which impaired trafficking of T cells may occur. We also expect to deliver an optimized human therapeutic enzyme displaying the requisite catalytic function and pharmacological properties (stability, PK/PD) for subsequent clinical evaluation (Aim 3).