Hydrogen sulfide inhibits recruitment of monocyte-derived tumor associated macrophages in glioblastoma by downregulating CXCL12

Tumor associated macrophages (TAMs) directly contribute to the dismal prognosis of glioblastoma by preventing anti-tumor immunity and promoting tumor invasion and angiogenesis. Inhibiting TAM infiltration is a potential therapeutic strategy in glioblastoma, with several chemokine antagonists in early clinical development. Hydrogen sulfide, a gasotransmitter that regulates microglial accumulation in a wide range of CNS diseases, may be a novel therapeutic target to prevent TAM recruitment in glioblastoma. In this study, hydrogen sulfide concentrations were directly measured from 14 isocitrate dehydrogenase (IDH)-wildtype glioblastoma surgical samples and compared against overall survival as well as expression of TAM markers and chemokines. Effects of hydrogen sulfide donor therapy on survival and TAM recruitment were also examined in a genetically engineered mouse model of glioblastoma. High hydrogen sulfide concentrations conferred a survival benefit in IDH-wildtype glioblastoma, in association with reduced monocyte-derived TAM density and downregulation of CXCL12. These findings were validated by administering hydrogen sulfide donor SG1002 to an immunocompetent mouse model of glioblastoma, which improved survival, inhibited monocyte infiltration, and downregulated CXCL12. Finally, hydrogen sulfide donor treatment directly reduced CXCL12 expression in glioblastoma cells, diminishing their ability to recruit monocytes in vitro. Taken together, these results demonstrate that hydrogen sulfide signaling prevents monocyte-derived TAM accumulation in glioblastoma by inhibiting chemotaxis.