Abstract 5604: Targeting CD73 augments the efficacy of A2aR blockade in PTEN-deficient prostate cancer
Authors: De Velasco Marco A. , Kura Yurie , Ando Naomi , Sako Noriko , Sakai Kazuko , Schuller Alwin , Sachsenmeier Kris , Fujita Kazutoshi , Banno Eri , Nozawa Masahiro , Yoshimura Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: June 2022

Abstract
Extracellular adenosine is an immunosuppressive molecule that is generated from ATP by the CD39 and CD73 ectoenzymes and exerts its antitumor effects through its interaction with the adenosine 2A receptor (A2AR) on immune cells. Approaches to curtail the immunosuppressive effects of extracellular adenosine primarily target CD73 and A2aR. In this study, we examined the immunomodulatory effects and antitumor effects of CD73 and A2aR blockade in the context of PTEN-deficient prostate cancer. The immunomodulatory effects of anti-CD73 antibody blockade (aCD73) or A2aR inhibition with the small molecule inhibitor AZD4635 were characterized in transgenic mice bearing Pten-null prostate tumors after one week of dosing. qPCR-based tumor immune profiling revealed distinct differences between the treatment groups that were characterized by the enrichment of gene signatures related to T cell, natural killer cell, and NK T cell in AZD4635 treated mice and macrophage and B cell in mice treated with aCD73. Immunohistochemical analysis showed significant 2.5- and 4.6-fold increases of granzyme B positive immune cells in the cancer glands of aCD73 and AZD4635 treated mice, respectively. Efficacy studies showed that tumors from mice after long-term treatment with AZD4635 were characterized with high adenosinergic signatures and particularly increased levels of Nt5e, the gene encoding CD73. Treatment with aCD73 and AZD4635 alone or in combination led to tumor burden reductions of 4.4%, 15.1% and 16.7%, respectively, after four weeks of treatment and -8.58%, 4.6% and 29.5%, respectively after eight weeks of treatment. Additional analyses showed that androgen deprivation therapy induced an adenosine high signature, and increased Nt5e expression levels and CD73-positive infiltrating MDSCs/neutrophils. The efficacy of AZD4635 versus aCD73 plus AZD4635 was evaluated in an in vivo castration-sensitive model of Pten-null prostate cancer treated with apalutamide plus androgen deprivation therapy via surgical castration. In this model, mice were treated for eight weeks to allow for the progression to castration-resistant prostate cancer (CRPC) and in this setting, the treatment combination of aCD73/AZD4635 improved tumor burden reduction to 34.3% from 23.1% in AZD4635 treated mice. Moreover 75% (6/8) of mice treated with aCD73/AZD4635 had tumor burden reductions greater than 30% relative to vehicle treated controls versus 28.6% (2/7) of mice in the AZD4635 only group. Our findings show that extracellular adenosine is a key immunosuppressive molecule in PTEN-deficient prostate cancer and provide evidence that implicates adenosinergic signaling via CD73 as a contributing factor to decreased efficacy of A2aR blockade and progression to CRPC.
Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Noriko Sako, Kazuko Sakai, Alwin Schuller, Kris Sachsenmeier, Kazutoshi Fujita, Eri Banno, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Targeting CD73 augments the efficacy of A2aR blockade in PTEN-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5604.