Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer

Abstract

PURPOSE Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)–expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies ( P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = −0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells ( P < .005) and lower numbers of activated NK cells ( P < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353 ).

Dickkopf-1 is a Prognostic Biomarker and Correlated With Immune Infiltrates in Head and Neck Squamous Cell Carcinoma

“…Sui et al reported that DKK 1 impairs the tumor response to PD-1 blockade by inactivating CD8 + T cells in colorectal cancer [14]. Another study demonstrated that metastatic castration-resistant prostate cancer (mCRPC) tumors with high DKK1 expression exhibit a CD8 + T-cell-poor tumor microenvironment in ltrated with immature M0 macrophages and M2 macrophages [31]. Our analysis and the results of these study have a mutual veri cation effect.…”

“…Zhang et al [39] demonstrated that MT1-deletion can be an independent prognostic factor in hepatocellular carcinoma. David et al found that DNA methylation as a likely mechanism that governs DKK1 expression in metastatic castration-resistant prostate cancer [31]. A further implication of this result is that elevated DKK1 could be a resistance mechanism to therapeutic DNA methyltransferase inhibition, which is currently being tested in clinical trials.…”

Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

“…In fact, a phase II trial combining pembrolizumab with the CXCR1/CXCR2 antagonist navarixin in mCRPC patients is currently ongoing (NCT03473925). Additionally, Wise and colleagues described Dickkopf-1 (DKK1) gene expression as a novel contributor to the immunosuppressive TME of mCRPCs with low AR and without neuroendocrine signaling [ 118 ]. These data provided the rationale for an ongoing clinical trial targeting DKK1 in mCRPC (NCT03837353).…”

Safety, Efficacy, and Biomarker Results from a Phase Ib Study of the Anti-DKK1 Antibody DKN-01 in Combination with Pembrolizumab in Advanced Esophagogastric Cancers

“…17 DKN-01 (Leap Therapeutics, Cambridge, Mass., USA) is a humanized IgG4 monoclonal antibody that binds and neutralizes circulating DKK1 and has demonstrated nonclinical singleagent activity in DKK1-expressing tumor models. 18 Combination work with anti-PD-1 agents suggested enhanced activity in murine models. 17 We conducted a phase Ib trial exploring the safety and preliminary clinical activity of DKN-01 alone or in combination regimens in previously treated, advanced EGC patients.…”