Defining the monocyte subset transcriptional signature associated with progression during androgen-target therapy in prostate cancer patients.

Abstract

157 Background: Myeloid-derived circulating monocytes are emerging as cells of interest in cancer biology. The role of circulating monocytes in human Prostate Cancer (PCa) is poorly understood. Here we asked what is the association of monocyte-specific subsets and their transcriptional signatures with PCa progression during (AR)-target therapy. Methods: Single-cell RNAseq analysis were performed in blood monocytes from 4 patients at two specific time points over their clinical, course: T1)responding to next generation androgen receptor signaling inhibitors (e.g. abiraterone or enzalutamide) as reflected by a decline in serum PSA and/or radiographic response, and T2)progressing through treatment as detected by increases in the serum PSA concentration and/or radiographic signs of progression .PBMC were subjected to Ficoll-purification, and FACS sorted to exclude dead cells and cells expressing B- and T- lineage markers. Samples were then pooled using a BD™ Single-Cell Multiplexing Kit. The samples for scRNA-seq analysis included monocytes defined as classical CD14++CD16−, intermediate CD14+CD16+, and non-classical CD14low/-CD16+++. Results: We have observed nine (9) transcriptionally-defined clusters.Clusters 0, 1, 4, 5, and 8 mapped closely to that of classical monocytes with high expression of CD14and low expression of FCG3RA (CD16). Clusters 2 and 3 mapped closely to that of NK cells with high expression of FCG3RA(CD16) and KLRB1(CD161), and clusters 6 and 7 corresponded to CD14low FCG3RAhigh SIGLEC10+ monocytes. Importantly, our preliminary data revealed a decrease in the percentage of cells in clusters 2 and 6 and an increase in the percentage of cells in cluster 4 in progressing patients (T2). At the transcriptional level, the three main clusters (classical, non-classical, NK-like) were distinguished by 32, 33, and 72 genes, respectively. Our preliminary findings show that progression was associated with several innate immune transcripts while cytotoxic genes were associated with response to Enzalutamide. Conclusions: These data suggest that monocytes transcriptional signature may be reshaped by PCa. Further study of monocytes in PCa progression are warranted.