Glioma stem cell regulator S100A4 modulates gbm immune landscape

Abstract

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is virtually incurable. Immunotherapy is a promising new approach to treat GBM as it harnesses one’s own immune system to recognize and kill aberrant cancer cells. Unfortunately ongoing trials with immunotherapies show disappointing results in most glioma patients. GBM has highly immune-suppressive microenvironment. Consistently, mesenchymal subtype, the subtype with worst prognosis, has a strong immune signature. We recently reported that S100A4 is necessary for human and mouse glioma initiating cell (GIC) self-renewal and tumor growth, and that S100A4 is a master regulator of mesenchymal transition in GBM. Importantly, we report that S100A4 regulates expression of cytokines that affect TAM infiltration and polarization towards tumor-promoting phenotype. Consistently, TCGA and IVY-GAP data analyses indicate that S100A4 expression is strongly correlated with GBM patient survival, the mesenchymal subtype, and tumor-promoting TAM (tumor-associated macrophage) and MDSC (myeloid-derived suppressor cell) marker expression (such as CD163, CD204/MSR1, IL10, CD11b, S100A8, and S100A9). S100A4 expression and TAM marker expression strikingly overlap in perivascular and perinecrotic regions, previously reported niches for GICs. Interestingly there is no correlation between S100A4 expression and markers of microglia. Through single cell RNA-sequencing analyses of human GBM samples, we now have evidence that S100A4 is expressed in both glioma cells and infiltrating myeloid cells. When S100a4 is knocked down in mouse glioma cells and transplanted into syngeneic mice, tumor promoting myeloid cell numbers are significantly reduced. We are currently testing the role of S100A4 in bone marrow derived myeloid cells and elucidating the molecular mechanism of S100A4 function. Our unpublished observations strongly suggest that S100A4 is a critical regulator of GBM immune landscape and may be key node that links GICs, mesenchymal transition, and the myeloid cell infiltration.