Abstract 3923: Targeting immunosuppressive TREM2+tumor associated macrophages in prostate cancer
Authors: Lee Alex J. , Adusei Kenneth , Praharaj Monali , Shen Fan , Wang Xiaoxu , Bhatia Kaavya , Nirschl Thomas , Zarif Jelani C. 
Published: March 2024

Abstract
With over 250,000 new cases annually, prostate cancer (PCa) is amongst the most diagnosed cancers in the United States. Despite a near-perfect 5-year survival rate in patients with localized disease with androgen deprivation therapy (ADT), about 10-20% of patients on ADT eventually develop castration-resistant prostate cancer (CRPC). Immunotherapies are typically ineffective in treating these treatment-resistant patients due to the abundance of immunosuppressive tumor-associated macrophages (TAMs) and lack of infiltrating lymphocytes. We propose to target these immunosuppressive macrophages through the triggering receptor expressed on myeloid cells 2 (TREM2), which has been identified as a major mediator of suppressive macrophage function but has not been studied in the context of PCa and CRPC. For this study, we analyzed publicly available RNA-seq datasets to query for TREM2 expression amongst patients with a range of prostate cancer disease states and cell types, measured tumor growth kinetics in two subcutaneous models of prostate cancer, and compared tumor immune infiltrates by flow cytometry. Our analysis of the TCGA prostate adenocarcinoma (PRAD) and the Stand Up to Cancer/Prostate Cancer Foundation (SU2C/PCF) datasets implicate TREM2 expression with prostate cancer progression, by Gleason score and progression-free status, and with worse overall survival of patients with metastatic CRPC (mCRPC). Manual curation and analysis of 10 single-cell RNA-seq datasets with a total of 84 patients, encompassing primary PCa, CRPC, and mCRPC indicate that TREM2 is highly and specifically expressed on TAMs in prostate cancer, with macrophages from patient-matched tumor samples expressing higher TREM2 compared to normal adjacent tissue. B6CaP tumors, with a luminal cytokeratin profile, high AR expression, and high Myc expression, show slower tumor growth in Trem2−/− mice compared to tumors in Trem2wt mice. On the other hand, RM1 tumors show no difference in growth kinetics on Trem2−/− mice. A major difference between the B6CaP and RM1 tumor microenvironments is the level of macrophage infiltration, where only 2-5% of immune cells in RM1 tumors are macrophages, compared to the 40-50% in B6CaP tumors. RM1 cells co-implanted with Trem2−/− macrophages show slower tumor growth, compared to tumor cells co-implanted with Trem2wt macrophages, confirming the role of Trem2-expressing macrophages in mediating tumor growth. Consistent with previous reports of suppressive Trem2 signaling, we also observed higher levels of inflammatory cytokine production in ex vivo stimulated Trem2−/− TAMs. By targeting TREM2 in prostate cancer, we find that TAMs are less suppressive, more inflammatory, and permit cytotoxic lymphocyte infiltration to enhance anti-tumor responses by synergizing with chemo and immune checkpoint therapy.
Citation Format: Alex J. Lee, Kenneth Adusei, Monali Praharaj, Fan Shen, Xiaoxu Wang, Kaavya Bhatia, Thomas Nirschl, Jelani C. Zarif. Targeting immunosuppressive TREM2+tumor associated macrophages in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3923.