Background:Chemerin, a leukocyte chemoattractant, signals through CMKLR1 on immune cells. Its role in tumor immunology is increasingly recognized. Prior evidence from our group suggests chemerin has tumor-intrinsic and immune effects, recruiting T and NK cells to the tumor microenvironment (TME). We used a real-world clinicogenomic dataset to characterize chemerin and related gene expression in PCa.

Methods:The Tempus Lens Platform (Tempus AI, Chicago, IL) was used to derive a cohort of de-identified PCa cases with clinical and genomic data. Data was analyzed in Tempus Workspaces using the tempusverse suite of R packages. In a pre-clinical study, chemerin-overexpressing TRAMP-C1 and vector control tumors were subcutaneously engrafted into mice. Tumor-infiltrating leukocytes (TILs) were analyzed by single-cell RNA sequencing (scRNA-seq).

Results:We retrospectively identified 311 men with PCa who underwent standard-of-care tumor genomic analysis, including WT bulk RNAseq. Chemerin expression was lower in metastatic sites (lymph nodes [LNs], bones, soft tissues) relative to primary prostate tumors (p<2.2e-16). Chemerin expression decreased linearly with increasing pathologist-estimated tumor purity (p=5.6e-5). A subset of cases with tumor purity > 70% (n=163) were selected for co-expression analysis. CMKLR1 and genes known to contribute to the coordinated anti-tumoral immune response (eg CD8, GZMB, CD86, etc) were significantly correlated with chemerin expression, as was the tumor suppressor PTEN (see table). In subset analysis of tumors by metastatic site similar correlations held in lung, bone, and LN metastases. Trends towards improved rwOS were seen in subset analyses favoring high chemerin expression though were not significant following risk-set adjustment. In mice, chemerin overexpressing tumors showed increased expression of cytotoxicity, activation, trafficking, and effector genes in TILs by scRNAseq, further corroborating these correlations.

Conclusions:We present the first real-world genomic analysis of chemerin in PCa. Chemerin is significantly downregulated in metastatic PCa sites compared to primary tumors. Higher chemerin correlated with a potent effector cell gene pattern, inline with our preclinical evidence of a chemerin-CMKLR1-PTEN tumor suppressive axis. In total, these data further suggest that chemerin is a key determinant of an immunologically “hot” TME in PCa, and may have relevance in clinical outcomes. To this end, a chemerin-based therapeutic for PCa is currently in development by Pixie Bio (St. Louis, MO).

All Spearman correlation values represent positive correlations.

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