Abstract
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.
Highlights
Therapies targeting tumor-fueling androgens have been mainstay treatments of advanced prostate cancer (PCa) for almost 5 decades
Expression of PD-L1/PD-1 in circulating innate immune and T cells is a useful prognostic indicator for aggressive tumor types and Ipilimumab responses [10,11], no such studies have been reported for castration-resistant prostate cancer (CRPC)
To determine if PD-L1 pathway targets are increased after ENZ treatment, PD-L1/2 and PD-1 were assessed by flow cytometry on dendritic cells (DC) and T cells isolated from a small cohort of metastatic CRPC patients who were ENZ naïve or classified as either “progressing” or “responding” to ENZ
Summary
Therapies targeting tumor-fueling androgens have been mainstay treatments of advanced prostate cancer (PCa) for almost 5 decades. Whereas Ipilimumab induced >50% PSA decline in 8 out of 50 men with metastatic CRPC [6], anti-PD1 treatment failed to produce an objective response in a separate small trial of 17 CRPC patients [7]. These data and the strong correlation between tumor expression of the PD-1 ligand, PD-L1, and positive responses to PD-1 blockade in other cancer types have suggested that the poor results testing anti-PD-1 therapy in CRPC may be due to the lack of PD-L1 expression in PCa tumors [7,8,9]. It remains unknown whether patients with ENZ resistant (ENZR) CRPC may be a more relevant cohort to study the efficacy of anti-PD-1 therapies, as expression of PD-L1 on ENZ resistant CRPC and the effects of ENZR tumors on the PD-L1/PD-1 pathway in circulating antigen presenting cells or T cells has not been reported
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