Sphingosine-1-phosphate receptor 1 (S1P1) loss mediates T cell sequestration in bone marrow in the setting of intracranial tumors: a novel mode of cancer-induced immunosuppression

Abstract

Abstract Glioblastoma (GBM), the most lethal primary brain tumor, proves one of the most immunosuppressive solid tumors. Consequently, immune-based interventions, including immune checkpoint blockade, have largely failed to benefit patients with GBM. Recently, we characterized severe lymphopenia and lymphoid organ contraction in treatment-naïve patients and mice with GBM. Remarkably, bone marrow (BM) proves the lone lymphoid organ not subject to T cell disappearance, instead harboring high numbers of the previously missing T cells. Other tumors, including lung, melanoma, and breast cancers, also accumulate T cells in marrow, but only when these tumors are introduced intracranially. In this study, we sought to determine the mechanism mediating T cell sequestration in the context of intracranial tumors. We found that T cells in the BM of tumor-bearing mice had significantly lower levels of surface sphingosine-1-phosphate receptor 1 (S1P1) compared to controls. Mice that were genetically modified to stabilize S1P1 on the surface of their T cells were resistant to T cell sequestration. Moreover, liberated T cells from these mice were able to synergize with a T cell activating 4-1BB agonist to significantly prolong median survival in GBM mice. Here we describe a novel mode of cancer-induced T cell dysfunction contributed specifically by the intracranial microenvironment: S1P1-mediated BM T-cell sequestration. These findings suggest that the immunoprivileged brain harbors unique mechanisms, usurped by intracranial tumors, for preventing T cell entry into the CNS to favor immune escape. Reversal of such sequestration is anticipated as a promising immunotherapeutic adjunct for both primary brain tumors and brain metastases.