BSLD-04 PROLIFERATION AND SURVIVAL OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA IN THE CENTRAL NERVOUS SYSTEM

Abstract T cell acute lymphoblastic leukemia (T-ALL) has a high incidence of spread to the central nervous system (CNS), particularly the meninges. Although all children diagnosed with T-ALL receive CNS-directed chemotherapy, these treatments induce substantial neurotoxicity, and relapsed disease often originates in the CNS. Development of safer CNS-directed therapeutics warrants a better understanding of molecular events supporting T-ALL survival in the CNS. Our lab recently found that T-ALL expression of integrins VLA4 and LFA1 suppresses proliferation of leukemia cells in the CNS. Additionally, we found that we can stimulate proliferation of integrin-expressing T-ALL using LFA1- and VLA4- blocking antibodies, and that integrin blockade synergizes with chemotherapy targeting proliferating cells. Previous studies have shown that cancer cells may enter a non-proliferative or quiescent state to survive in nutrient-poor environments. Furthermore, in many cases, cancer cells must first be anchored to stromal tissue to receive signals that induce quiescence. We postulate that integrin expression allows T-ALL to contact the meningeal stroma and receive secondary immunosuppressive signaling. We have determined that meningeal cells express the canonical LFA1 and VLA4 ligands, ICAM1 and VCAM1 respectively. We will block these by intrathecal infusion of blocking antibodies to determine if this leads to increased leukemia proliferation. We are also investigating the signals involved in proliferation suppression, and postulate that the expression of T-cell checkpoint molecules might be important. We have carried out bulk RNA-Seq analysis and find that CNS residing T-ALL cells express several checkpoint molecules, including SLAMF6. We are actively testing the importance of these to T-ALL CNS specific proliferation suppression, by antibody blockade and CRISPR knock-out. We expect to identify novel therapeutic targets for T-ALL CNS disease through this study.