Attwood, K. | Search bioRxiv

bioRxiv2021

Racial differences in androgen metabolism and receptor signaling in prostate cancer

Dihydrotestosterone (DHT) and testosterone (T) mediated androgen receptor (AR) nuclear translocation initiates transcription of AR target genes that are pivotal for prostate cancer (PrCa) development and progression. Here we provide data indicating that in contrast to European American (EA) men, African American (AA) men with localized PrCa can exploit an alternative progesterone-androsterone-5-androstanedione pathway for DHT biosynthesis. Enzymes that are involved in alternate pathways of DHT biosynthesis are elevated in PrCa tissues from AA men, compared to EA men, and also correlated with increased serum DHT levels. In addition, higher serum DHT levels reflect increased RNA expression of AR target genes in PrCa tissues from AA men. Interestingly, serum T but not DHT levels are significantly lower in AA men compared to EA men with PrCa. Furthermore, serum progesterone and related intermediate metabolites levels that are produced during alternate pathways of DHT biosynthesis are significantly lower in AA men with PrCa and associated with a shorter time to disease progression. These data highlight that androgen biosynthesis is altered in therapy naive localized PrCa in AA men, and can potentially serve as prognostic indicators of disease progression. SignificanceOur work provides a rationale to examine potential pharmacological interventions that target androgen biosynthesis and AR signaling earlier in the disease continuum in AA men with PrCa. Additionally, our study lays the groundwork for developing serum measurements of intermediate androgen metabolites as PrCa prognostic biomarkers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/437727v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@932dd0org.highwire.dtl.DTLVardef@a4cca0org.highwire.dtl.DTLVardef@1764be4org.highwire.dtl.DTLVardef@1708a63_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

A circulating T-cell differentiation marker to predict response to immune checkpoint inhibitors

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI will markedly improve current treatment regimens. Here, we investigated a role of CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, in predicting response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increased the frequency and T-cell receptor clonality of the peripheral CX3CR1+CD8+ T-cell subset that included an enriched repertoire of tumor-specific and tumor-infiltrating CD8+ T cells. Furthermore, an increase in the frequency of the CX3CR1+ subset in circulating CD8+ T cells early after initiation of anti-PD-1 therapy correlated with response and survival in patients with non-small cell lung cancer (NSCLC). Taken together, these data support T-cell CX3CR1 expression as a blood-based dynamic biomarker to predict response to ICI therapy.

immunology↗