T cell mediated dysregulation of bone marrow hematopoiesis in Glioblastoma 2260498

Abstract

Abstract Introduction Glioblastoma (GBM) is an aggressive brain cancer which induces severe systemic immunosuppression. Systemically, immune organs including the thymus and spleen involute, severe T cell lymphopenia occurs, and significant numbers of T cells are sequestrated within the bone marrow. The mechanisms underlying and linking local and systemic immunosuppression remain poorly understood. In particular, mechanisms governing T cell sequestration in the bone marrow of glioma-bearing subjects is understudied. Methods We evaluated the brain-bone marrow axis in GBM. Results One possible mechanism linking the TME to systemic immune derangements is the process of hematopoiesis in the bone marrow. Hematopoiesis results in generation of immune cells from hematopoietic stem and progenitor cells (HSPCs). Given that significant numbers of T cells are sequestrated in this delicate niche in glioma-bearing subjects, it is possible that their presence is troublesome. We seek to understand how T cell sequestration affects bone marrow function. To induce T cell sequestration, gliomas may impact the immune system either though release of soluble factors or via innervation. To distinguish between these possibilities, we employed parabiosis which is the surgical joining of two mice. When linking the circulation of GBM-bearing and tumor-naïve mice, we found that T cell sequestration occurred only in the bone marrow of GBM-bearing parabionts. This implicates innervation as an upstream mediator of T cell sequestration. Our preliminary data also demonstrate that the sequestrated T cells within the bone marrow of glioma-bearing mice directly impact HSPC numbers. Moreover, we connect the role of neutrophils and the brain-bone marrow innervation as upstream regulators of T cell sequestration into the bone marrow of GBM-bearing mice. Conclusion Our studies will shed light on novel mechanisms of brain-bone marrow communication and identify targets that can be leveraged to improve both local and systemic immunity in GBM. Funding Source NIH K99/R00 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)