Immu-12. t cell sequestration in posterior fossa tumors

Abstract INTRODUCTION T cell dysfunction contributes to immune escape in patients with cancer and is particularly severe in CNS tumors. T cell sequestration is a contributing mechanism of T cell lymphopenia and lymphoid organ contraction occurring in treatment naive patients and mice with Glioblastoma. Our group demonstrated that this phenomenon is mediated by loss of S1P1 surface expression on T-Cells within the bone marrow. We demonstrated in murine models that reversing T cell sequestration via stabilization of surface S1P1 licenses T cell activating therapies. As pediatric brain tumors much more commonly involve the posterior fossa and brainstem, the present work set out to assess whether T cell sequestration also occurs in tumors located in the cerebellum (medulloblastoma, high grade glioma). METHODS CT2A murine glioma cells were orthotopically implanted into the posterior fossa of C57BL/6 mice. Blood, spleen, and bone marrow were analyzed when tumors became sizable (Day 18-21). Flow cytometry was utilized to measure total, CD4+, and CD8+ T cell counts, as well as the proportion of T cells expressing surface S1P1. RESULTS Compared with mice injected with methylcellulose, mice bearing cerebellar CT2A tumors demonstrated significantly decreased splenic weight, increased total, CD4, and CD8 T cell counts in the bone marrow, and a decreased proportion of surface S1P1 expressing T cells within the bone marrow. CONCLUSIONS T cell sequestration within the bone marrow associated with loss of surface S1P1, as previously demonstrated in high grade tumors of the forebrain, also occurs with tumors implanted into the cerebellum, suggesting that the genesis T cell sequestration is independent of location within the brain. Future work on this project will add additional tumor histology to our analysis as well as measuring the effects of S1P1 stabilization on response to T cell activating therapies in these models of cerebellar tumors.