Abstract 1071: Targeting A2aR in mouse Pten-deficient prostate cancer

Abstract

Inactivation of PTEN occurs frequently in advanced human prostate cancer and can promote an immunosuppressive tumor microenvironment (TME). Extracellular adenosine can be produced by tumors which can in turn modulate anti-inflammatory and immunosuppressive effects via interactions with the A2a receptor (A2aR). Here, we used a transgenic mouse model of Pten-deficient prostate cancer to characterize adenosine-mediated immunosuppression in the TME and evaluate the effects of A2aR blockade. Transcriptomic analysis of normal wildtype prostate and Pten-deficient prostate tumors revealed enriched signatures for genes downregulated after a A2aR knockdown or upregulated after A2aR stimulation. Moreover, androgen withdrawal led to increased expression of the A2aR-stimulated responsive genes Cxcl2/3/5, Il1b, S100a8, Ptgs2 and Thbs1. Immunohistochemical staining of CD73, the ecto-enzyme responsible for producing extracellular adenosine, showed heterogeneous staining ranging from negative to focally strong in epithelial cancer cells and was strongly expressed in immune cells. A2aR was also strongly expressed on immune infiltrates. We used the oral A2aR antagonist AZD4635 to determine the immunosuppressive activity of extracellular adenosine and evaluate its antitumor activity in the context of castration-naïve (CNPC), castration-sensitive (CSPC) and castration-resistant (CRPC) prostate cancer. Four weeks of treatment with AZD4635 led to a 12.1% (P=0.140) reduction of tumor burden compared to control mice. Notably a subset of these mice (4/8) had tumor reductions greater than 20%. For the CSPC/CRPC models, mice were orchidectomized and treated with apalutamide with or without AZD4635 for four or eight weeks to represent CSPC or CRPC phenotypes, respectively. In these settings, treatment with AZD4635 improved the reduction of tumor burden by 16.4% (P=0.165) and 16.8% (P=0.123) in CSPC and CRPC, respectively. Despite similar reduction rates between the cohorts, a greater proportion of AZD4635 treated mice were below the median distribution in the CRPC setting compared to the CSPC setting, 50% (4/8) vs 70% (7/10), respectively. Immunophenotyping showed an increase in the abundance of dendritic cells in tumors and tumor draining lymph nodes of AZD4635-treated mice in the CPNC setting. Whereas a shift in M2 to M1 macrophage, decrease of PD1hi CD8 T cells and an increase in genes related to cytotoxic lymphocyte activity (Gzma, Gzmb, Prf1, Klrg1, and B3gat1) were observed in AZDD4635 treated mice in the CRPC setting. Decreased expressions of immunosuppressive genes related to T regulatory cells (Ctla4, Il2ra, Itga2, Tigit, Foxp3) were noted in both CSPC and CRPC settings. Our findings show that targeting extracellular adenosine with AZD4635 is effective in a subset of mouse Pten-deficient tumors and provides evidence that suggests context-specific immune modulating activity by extracellular adenosine in prostate cancer. Citation Format: Marco A. De Velasco, Yurie Kura, Noriko Sako, Naomi Ando, Kazuko Sakai, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Alwin Schuller, Kazuto Nishio, Hirotsugu Uemura. Targeting A2aR in mouse 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 1071.

Moving toward improved immune checkpoint immunotherapy for advanced prostate cancer

“…Peripheral levels of PMN‐MDSCs are elevated in patients with mCRPC and are recruited to tumors where they accumulate 144–146 . Hypoxia, which is a hallmark of cancer and is also prevalent in human CRPC, can also increase levels of extracellular adenosine to recruit myeloid cells into tumors 147–150 . In tumors, PMN‐MDSCs produce several suppressive molecules such as IL‐23, TGF‐β, arginase 1, IL‐10, and ROS that dampen effector T‐cell function and induce the expansion of Tregs 145,151 .…”

“…[144][145][146] Hypoxia, which is a hallmark of cancer and is also prevalent in human CRPC, can also increase levels of extracellular adenosine to recruit myeloid cells into tumors. [147][148][149][150] In tumors, PMN-MDSCs produce several suppressive molecules such as IL-23, TGF-b, arginase 1, IL-10, and ROS that dampen effector T-cell function and induce the expansion of Tregs. 145,151 PMN-MDSCs also inhibit T-cell cytotoxic activity by producing CCL4 and CCL5 to recruit Tregs in tumors.…”

A phase II study (AARDVARC) of AZD4635 in combination with durvalumab and cabazitaxel in patients with progressive, metastatic, castration-resistant prostate cancer

“… 23 AZD4635 has shown antitumor activity (reduction of tumor burden compared with control mice) in PTEN -deficient prostate cancer models showing evidence of immune modulation by extracellular adenosine in prostate cancer. 24 In the phase I study, AZD4635 has demonstrated clinical activity in mCRPC, and appears to have increased efficacy in combination with anti-PD-L1 in mCRPC due to increased immune activation compared with single-agent AZD4635. 25 Taken together, AZD4635 treatment results in a less immunosuppressive TME and may complement other immune-targeting drugs to enhance clinical response.…”