Deconstructing the immunomodulatory checkpoints in metastasis to the cerebrospinal fluid

forthcoming

While the healthy brain is largely devoid of lymphoid cells, the surrounding cerebrospinal fluid (CSF) is normally populated by lymphocytes. CSF hosts an array of threatening pathologies, including leptomeningeal metastasis with unusually poor prognosis. Despite the presence of immune cells, including CD8 T lymphocytes, this metastasis site does not respond to immunotherapy. My preliminary data demonstrate that the molecular profile and phenotypic behavior of these CSF CD8 T cells is inconsistent with conventional immune exhaustion. I hypothesize that CSF is an inherently immunosuppressive environment, protecting the brain from inflammatory insults directly by its composition. In CSFcheck, we will identify the individual components of the CSF that convey its immunosuppressive essence and manipulate the core CD8 T cell gene networks to disrupt the consequences of this phenomenon (Aim 1). We will investigate the fate, lifespan, and function of these cells after the metastasis encounter (Aim 2). Combining my experience with cutting-edge mouse immune modeling, systems-level computation, and functional assessment of human tissues, we will chart the immunosuppressive nature of the CSF and uncover the molecular pressure that CD8 T cells undergo upon entry to the CSF. This work will challenge and refine our understanding of the central nervous system immune privilege and communication with the periphery, exposing novel immunoregulatory mechanisms in metastasis that go beyond T-cell exhaustion.