title: 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.
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Bishop
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sio
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada.
authors.forename: Arkhjamil
authors.initials: A
authors.lastname: Angeles
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Roberts
authors.affiliation: Department of Medicine, Division of Medical Oncology, BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Arun A
authors.initials: AA
authors.lastname: Azad
authors.affiliation: Department of Medicine, Division of Medical Oncology, BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000378:metabolism*; D001549:Benzamides; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009570:Nitriles; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D001549:Benzamides; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide