Sexually dimorphic effect of h-ferritin genetic manipulation on survival and immune cell infiltration in a mouse model of glioblastoma

Abstract Iron plays a crucial role in promoting tumor growth. Recent research has shown that H-ferritin (FTH1), traditionally recognized as an iron storage protein, can transport iron to GBM cancer stem cells, reducing their invasion activity. Moreover, binding of extracellular FTH1 to human GBM tissues, and brain iron delivery in general, has been found to have a sex bias. This raises questions addressed in this study about whether H-ferritin levels extrinsic to the tumor can affect tumor cell pathways and if this impact is sex-specific. Systemic Fth1+/- mice were orthotopically implanted with mouse GBM cells (GL261). Littermate Fth1 +/+ mice were controls. Survival was evaluated and the tumors were subjected to next-generation sequencing protocols. We analyzed resulting data utilizing murine Microenvironment Cell Population (mMCP) method. mMCP estimates abundance of tissue infiltrating immune and stromal populations based on cell-specific gene signatures. Female Fth1+/- mice had significantly poorer survival than control females. Fth1 genetic status had no effect on survival in males. mMCP analysis revealed a significant reduction in T cells and CD8+ T cell infiltration tumors of Fth1+/- females as compared to Fth1+/+. Mast and fibroblast cell infiltration was increased in females and males with Fth1+/- background, respectively, compared to Fth1+/+ mice. Genetic manipulation of Fth1 which leads to reduced systemic levels of FTH1 protein had a sexually dimorphic impact on survival. Fth1+/- significantly worsened survival in females but not in male GBMs. Furthermore, genetic manipulation of Fth1 significantly affected tumor infiltration of T-cells, CD8+ T cells, fibroblasts, and mast cells in a sexually dimorphic manner. These results demonstrate a role for FTH1 and presumably iron status in establishing the tumor cellular landscape that ultimately impacts survival and further reveals a sex bias that may inform the population studies showing a sex effect on the prevalence of brain tumors.