Intracranial tumors skew bone marrow hematopoiesis

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival of 15-21 months. It remains universally fatal and has proven refractory to immunotherapies that are successful in treating other solid cancers. Two major contributing factors to the failure of immunotherapies to treat GBM include its ability to cause systemic lymphopenia and a tumor microenvironment (TME) that is heavily infiltrated by immunosuppressive myeloid populations. In this study, we used flow cytometry to detect changes in bone marrow hematopoiesis that occur in mice with intracranial tumors. Specifically, there are decreased numbers of common lymphoid progenitors and increased numbers of granulocyte macrophage progenitors in mice with intracranial tumors compared to tumor-naïve mice and mice with subcutaneous tumors. Intracranial breast and lung metastasis models behave similarly. Moreover, the myeloid to T cell ratio in the TME of intracranially-implanted glioma is four-fold higher than the ratio in subcutaneously-implanted glioma. The hematopoietic changes may thus indicate a common origin for the systemic and TME-localized myeloid skewing that occurs.The mechanism through which tumors in the intracranial compartment skew bone marrow hematopoiesis is an area of intense interest. In this study, we demonstrate that hematopoietic skewing is not mediated via adrenergic signaling, IL-1beta signaling, nor the CXCR4-CXCL12 axis. Cytokine array and ELISA data both indicate that elevated M-CSF in the bone marrow of mice with intracranial tumors may play a role in promoting myeloid progenitors at the expense of lymphoid progenitors. It is well known that these two lineages compete for survival factors in the hematopoietic niche and that giving one an advantage can decrease output of the other. Further study is needed to determine the role of M-CSF in myeloid skewing in GBM. While the nature of the local and systemic shift from lymphoid to myeloid populations remains a mystery, future immunotherapeutic efficacy will hinge upon our capacity to rescue systemic T cell populations and restrict their counterproductive interactions with myeloid cells in the tumor.