Immunomodulation of the Prostate Tumor Microenvironment Following Inorganic Arsenic Exposure.

Area of Science:

• Oncology
• Immunology
• Environmental Toxicology

Background:

• The tumor microenvironment (TME) critically influences prostate cancer (PCa) progression via stromal and immune cell interactions.
• Adipose-derived mesenchymal stromal cells (ASCs) are known to modulate immune responses.
• Inorganic arsenic (iAs), a common toxicant, is associated with immune suppression and cancer development, but its combined effect with ASCs on PCa immunity is unknown.

Purpose of the Study:

• To investigate the combined impact of ASCs and chronic inorganic arsenic (iAs) exposure on prostate cancer (PCa) progression and the tumor microenvironment (TME).
• To elucidate the mechanisms by which ASC-iAs crosstalk influences immune cell infiltration, gene expression, and tumor growth in a murine PCa model.

Main Methods:

• Utilized a Ras-driven murine PCa model (TC2Ras) to mimic aggressive, immune-interactive PCa.
• Assessed tumor growth, immune cell infiltration (flow cytometry), and transcriptomic changes (RNA-seq, qPCR) following ASC co-implantation and iAs exposure.
• Analyzed the effects of ASC-conditioned media on cancer cell viability.

Main Results:

• ASC-conditioned media enhanced TC2Ras cell viability, an effect counteracted by iAs.
• In vivo, ASC co-implantation with iAs led to increased tumor weight.
• ASC promoted infiltration of macrophages and CD4+ T cells, while iAs suppressed macrophages and myeloid-derived suppressor cells (MDSCs).
• Transcriptomic analysis revealed sustained IFNγ-IRF1 activation in ASC tumors and iAs-driven downregulation of adaptive immunity and upregulation of immune checkpoint genes (Pdcd1, Lag3).

Conclusions:

• ASC-iAs crosstalk significantly remodels the TME, promoting immune tolerance and chronic IFNγ signaling.
• This interaction potentially facilitates prostate cancer progression.
• The study reveals novel mechanisms by which environmental toxicants like iAs can influence cancer immunity through interactions with stromal cells.