PD-L1 is highly expressed in Enzalutamide resistant prostate cancer

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.

The Immune Checkpoint Regulator PD-L1 Is Highly Expressed in Aggressive Primary Prostate Cancer

“…Strikingly, Bishop and colleagues recently reported that CRPC patients resistant to enzalutamide showed elevated levels of PD-L1-expressing dendritic cells in blood (51). Additional cell line and xenograft experiments suggested that enzalutamide-resistant tumors might suppress immune response not only through intrinsic PD-L1 expression, but also via induction of PD-L1 expression on circulating dendritic cells.…”

CD73 Expression Is an Independent Prognostic Factor in Prostate Cancer

“…One factor that can influence the prognostic value of immune infiltrates is the immunosuppressive status of the tumor microenvironment (TME). T-cell function in prostate tumors can be severely attenuated, as evidenced by their inability to mediate cytotoxic function and secrete cytokines, and by the expression of exhaustion markers (12)(13). One of the most recently described immunosuppressive pathways involved in tumor progression is the CD73-adenosinergic pathway (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

The Changing Therapeutic Landscape in Metastatic Prostate Cancer

“…19 Bishop et al have demonstrated that non AR-mediated upregulation of PD-L1 expression occurs in both enzalutamide-resistant pre-clinical models and patients with prostate cancer. 20 In a recent phase II trial, patients who had progressed on enzalutamide were treated with the anti-PD-1 antibody pembrolizumab. 21 Three of the first 10 patients treated had rapid and significant decreases in PSA from pre-treatment levels of 46, 71, and 2,503 to <0.1.…”