Immunomodulation of the Prostate Tumor Microenvironment Following Inorganic Arsenic Exposure

The tumor microenvironment (TME) influences prostate cancer (PCa) progression through stromal and immune interactions. Adipose-derived mesenchymal stromal cells (ASCs) modulate immune tone, while inorganic arsenic (iAs), a widespread toxicant, is linked to immune suppression and carcinogenesis. Their combined impact on PCa immunity has remained unclear. Using a Ras-driven murine PCa model (TC2Ras, which mimics aggressive, immune-interactive PCa through constitutive Ras signaling), we assessed ASC and chronic iAs exposure effects on tumor growth, immune infiltration, and transcriptomic remodeling via flow cytometry, RNA-seq, and qPCR. ASC-conditioned media increased TC2Ras viability by up to 82%, an effect reversed by iAs (300-1000 ppb). In vivo, ASC co-implantation significantly elevated tumor weight in ASC + iAs tumors. ASC promoted approximately twofold macrophage and CD4⁺ T-cell infiltration, while iAs suppressed macrophages and MDSCs. We performed RNA-seq and qPCR, confirming that a sustained IFNγ-IRF1 activation (approximately eightfold) in ASC tumors occurred alongside an iAs-driven downregulation of adaptive immunity, as well as an upregulation of immune checkpoint genes (Pdcd1, Lag3). These findings demonstrate that ASC-iAs crosstalk remodels the TME toward immune tolerance and chronic IFNγ signaling, potentially facilitating tumor progression and revealing novel mechanisms by which environmental toxicants may influence cancer immunity through stromal cell interactions.