PU.1 Inhibition Appears to Restrain Murine Melanoma Growth by Promoting the CXCL9/10/11 - CXCR3 Network in Tumor-Associated Macrophages

The tumor microenvironment is essential in tumor growth/development. Tumor-associated-macrophages (TAMs) are often the most abundant immune cells in the microenvironment with a predominantly immunosuppressive phenotype, assisting tumor growth. Due to this, TAMs are an ideal immunotherapy target, but TAM-selective reagents are still to be discovered. Here, I used a small molecule inhibitor which likely blocks PU.1 (critical macrophage transcription factor) binding, modulating TAM activity in murine melanoma. PU.1 inhibitor DB2313 restrained syngeneic mouse tumor growth, increased natural killer cell and T-cell recruitment/tumor cell-specific T-cell infiltration, along with cytotoxic markers in tumors. Depleting TAMs blocked this recruitment. PU.1 inhibition increased mRNA expression of chemokines CXCL9/CXCL10 in TAMs. Blocking CXCL9 and its receptor CXCR3 seemed to silence the effect of PU.1 inhibition on tumor growth and T-cell/natural killer cell recruitment, suggesting the anti-tumor effect of PU.1 inhibition is dependent on the CXCL9/10/11-CXCR3 network. This study evaluates and explores a novel immunotherapy’s mechanism.