| Popis: |
The tumor microenvironment (TME) is a dynamic milieu comprised of various cell types and molecular complexes that eventually evolves to promote cancer cell proliferation, metastasis, and immune evasion. Myeloid cells are a key component of the TME and play key roles in initiating antitumor responses and coordinating with cells of the adaptive immune system. However, these cells are eventually hijacked by tumors and provoke local inflammation that results in chronic cancer-associated inflammation and immune escape. Extracellular adenosine (ecADO) is an immunosuppressive metabolite that is produced in tumors that binds the adenosine 2a receptor (A2aR) which is widely expressed in immune cells. Studies have shown that blocking A2aR signaling has the potential to enhance antitumor immunity by boosting T and NK cell immune responses. However, the relationship between ecADO and tumor-associated myeloid cells is less characterized. We previously reported on the antitumor activity of A2aR and CD73 blockade in preclinical models of Pten-null prostate cancer and their impact on T cell mediated responses. Here, we examine tumor-associated myeloid cell infiltration in models of castration-naïve (CNPC) and castration-resistant prostate cancer (CRPC) the impact of A2aR and CD73 blockade. Transcriptomic, flow cytometric, and immunohistochemical (IHC) profiling studies of CNPC and CRPC from conditional Pten-knockout (KO) and Pten/Trp53-double knockout (DKO) showed that tumor-infiltrating myeloid cells constituted a significant proportion of the prostate tumor microenvironment. CD11b+/Ly6G+ cells representing tumor associated neutrophils (TANs) and myeloid derived suppressor cells (MDSCs) were the most abundant immune cell type comprising 14.9% and 32.1% of the total population, and 46.5% and 69.7% of infiltrating leukocytes in in CNPC and CRPC, respectively. Furthermore, CD11b+/Ly6G+ expressed high levels of CD73. Pte-null prostate tumors were characterized with enriched adenosine signaling signatures which were greater in CRPC compared to CNPC. Treatments with the A2aR inhibitor AZD4635 alone and in combination with CD73 antibody blockade reduced adenosinergic genes as well as genes associated with TAN/MDSC immunosuppressive functions. Additionally, tumors from treated mice exhibited improved T cell mediated cytotoxicity. Together, our findings indicate that tumor associated myeloid cells are an additional source of ecADO contributing to immune suppression which can be targeted with A2aR and CD73 inhibitors. Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Noriko Sako, Kazutoshi Fujita, Kazuko Sakai, Alwin G. Schuller, Kris F. Sachsenmeier, Masahiro Nozawa, Eri Banno, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Targeting tumor infiltrating myeloid cells in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5155. |
