Immunoprofiling of prostate cancer infiltrate

Tumor associated macrophages (TAMs) are correlated with the progression of prostatic adenocarcinoma (PCa) but are still poorly described in this context. Here we applied high dimensional single-cell RNA-seq to profile the transcriptional landscape of TAMs in PCa. We identified a subset of tumor infiltrating macrophages that shows a dysregulation in transcriptional pathways associated with lipid metabolism. In human and mouse models of PCa this subset of macrophages expresses the scavenger receptor MARCO and is characterized by accumulation of lipid droplets. We identified a gene signature derived from MARCO-expressing TAMs that correlates with PCa progression and is associated with shorter disease-free survival. Mechanistically, we observed that lipid accumulation in TAMs is promoted by the secretome of cancer cells. Lipid-loading confers to tumor-conditioned macrophages the capability to promote cancer cell migration mediated by CCL6. Importantly, administration of high fat diet to tumor-bearing mice raises lipid accumulation in TAMs and affects their transcriptional profile. Finally, we demonstrate that the accumulation of lipids in macrophages is dependent on MARCO expression and we show that MARCO blockade hinders tumor growth and invasiveness in models of advanced PCa. Our findings provide evidence that lipid-loaded TAMs represent a new therapeutic target in PCa. Overall design: A total of six samples; two conditions (normal and tumor) and three patients.