P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression

Eilam Yeini,Galia Tiram,Henry Brem,Nitzan Albeck,Ron Sheinin,Thomas M Hyde,Sapir Golan,Prerna Magod,Asaf Madi,Ron Kleiner,Sabina Pozzi,Ronit Satchi-Fainaro,Zvi Ram,Dikla Ben-Shushan,Shlomit Reich-Zeliger,Dinorah Friedmann-Morvinski,Sahar Israeli Dangoor,Paula Ofek,Rachel Grossman

doi:10.1038/s41467-021-22186-0

Abstract

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.

Highlights

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis
We found that PD-GB4 cells facilitate the proliferation and migration of human microglia as well (Supplementary Fig. 1A, B), indicating the reciprocal activation of microglia following the interaction with GB cells in our models
This suggests that GB cells may induce microgliosis in the brain as a result of the neuroinflammation induced by their crosstalk

Summary

Introduction

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. The reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood We propose that these mechanisms involve adhesion molecules such as the Selectins family. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. GAMs may possess a pro-inflammatory/anti-tumorigenic phenotype in which they are phagocytic, cytotoxic, and bear antigen-presentation capabilities[8] This phenotype allows microglia/macrophages to attack transformedcancerous cells and harness cytotoxic T cells against the tumor. Mixed populations are found in GB tumors, GAMs contribute to immune-escape and promote tumor progression, and have been shown to actively enhance glioma growth and invasion, and secrete angiogenic factors[10]. This emphasizes the need for alternative or combination approaches[11]

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Conclusion