PD-L1 is Highly Expressed in Enzalutamide Resistant Prostate Cancer.
Efficacy of Enzalutamide (ENZ) in castration-resistant prostate cancer (CRPC) patients is short-lived. Immunotherapy like T cell checkpoint blockade may improve patient survival. However, when and where checkpoint molecules are expressed in CRPC and whether immune evasion is a mechanism of ENZ resistance remains unclear. Thus, we investigated whether clinically relevant immunotherapy targets, specifically PD-L1/2 , PD-1 and CTLA-4, are upregulated in ENZ resistant (ENZR) patients and in a pre-clinical model of ENZ resistance. We show for the first time that patients progressing on ENZ had significantly increased PD-L1/2+ dendritic cells (DC) in blood compared to those naïve or responding to treatment, and a high frequency of PD-1+T cells. These data supported our pre-clinical results, in which we found significantly increased circulating PD-L1/2+ DCs in mice bearing ENZR tumors compared to CRPC, and ENZR tumors expressed significantly increased levels of tumor-intrinsic PD-L1. Importantly, the expression of PD-L1 on ENZR cells, or the ability to modulate PD-L1/2+ DC frequency, was unique to ENZR cell lines and xenografts that did not show classical activation of the androgen receptor. Overall, our results suggest that ENZ resistance is associated with the strong expression of anti-PD-1 therapy targets in circulating immune cells both in patients and in a pre-clinical model that is non-AR driven. Further evaluation of the contribution of tumor vs. immune cell PD-L1 expression in progression of CRPC to anti-androgen resistance and the utility of monitoring circulating cell PD-L1 pathway activity in CRPC patients to predict responsiveness to checkpoint immunotherapy, is warranted.
Oncotarget. 2015; 6:234-242 [Epub]
Jennifer L. Bishop,1 Alexander Sio,1 Arkhjamil Angeles,1 Morgan E. Roberts,2 Arun A. Azad,3 Kim N. Chi,3 and Amina Zoubeidi,1,4
1. Vancouver Prostate Centre, Vancouver, BC, Canada 2. Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada 3. Department of Medicine, Division of Medical Oncology, BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada 4. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada