Abstract 3416: Androgen deprivation following JAK1/2 and PD-L1 inhibition improves antitumor efficacy in mouse models of Pten-deficient prostate cancer
Authors: De Velasco Marco A. , Kura Yurie , Ando Naomi , Sako Noriko , Sakai Kazuko , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: September 2020

Recently, the tumor suppressor PTEN has been shown to function as an immune modulator and its inactivation is associated with mediating tumor immune evasion. We previously examined the effects of programmed death-ligand 1 (PD-L1) immune checkpoint blockade (ICB) in transgenic mouse models of Pten-null prostate cancer. However, anti-PD-L1 monotherapy was largely ineffective in immunologically cold castration-naïve tumors from intact mice but showed some activity when administered to castrated mice. Our previous immune profiling studies also revealed that while androgen withdrawal increased tumor inflammation, it also mediated the recruitment and accumulation of immunosuppressive cells such as regulatory T cells, M2-polarized macrophages and myeloid-derived suppressor cells (MDSCs). Interleukin-6 (IL-6)/signal transducer and activator of transcription-3 (STAT3) signaling is a key immune modulating pathway that is upregulated in both intact and androgen deprived tumors. Here, we evaluate the effectiveness of targeting PD-L1 and JAK/STAT signaling in preclinical models of Pten-null prostate cancer. Intact tumor bearing conditional Pten-knockout were treated for four weeks with an a-PD-L1 blocking antibody (clone D265A, mouse/IgG1 kappa) and/or the JAK1/2 inhibitor, AZD1480. Pharmacological treatments targeting PD-L1 and JAK1/2 (PJ) combinations were also evaluated as concurrent therapy with androgen deprivation (AD) by orchidectomy (PJ+AD), and as sequential therapy; two weeks AD followed by PJ (AD&gt;PJ), and one week of PT followed by AD (PJ&gt;AD). Combined PD-L1/JAK followed by AD was the only treatment combination that improved antitumor immune responses over monotherapy. Notably, flow cytometry studies showed that combined PD-L1/JAK potently abrogated PD-L1 expression in circulating dendritic cells in all settings. Evidence for enhanced antitumor immune response in PJ&gt;AD was supported by increased numbers circulating effector memory CD8 T cells and CD355+CD8+ T cells (CD355 Class I MHC-restricted T cell-associated molecule (CRTAM) a marker for activated CD8 T cell), and increased CD8 T cell infiltration in tumors and a reduction of CD25+CD4+ regulatory T cells. The efficacy of the PJ&gt;AD treatment combination was further tested and confirmed in a subcutaneous syngeneic allograft model using mice grafted with tumor blocks from Pten-deficient castration-resistant prostate cancer tumors. Together these results indicate that pretreatment with combined PD-L1/JAK blockade can decrease the immunosuppressive effects of androgen withdrawal and have the potential to restore antitumor immune activity in Pten-deficient prostate cancer.

Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Noriko Sako, Kazuko Sakai, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Androgen deprivation following JAK1/2 and PD-L1 inhibition improves antitumor efficacy in mouse models of Pten-deficient prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3416.