Abstract 103: Prostate cancer bone metastasis: Therapeutic targeting of tumor associated macrophages
Authors: Hanyu Zhang, Shenglin Mei, Nathan E. Jeffries, Douglas M. Dahl, Chin-Lee Wu, Philip J. Saylor, David B. Sykes
Journal: Cancer Research (2024)

Abstract Introduction: Castration-resistant bone metastatic prostate cancer is a morbid and deadly disease with an exceedingly low response rates to available immunotherapies. Understanding the mechanisms behind immune evasion and tumor progression is critical to improving therapy. Historically, bone metastases have been challenging to model in the laboratory. Our foundational work was built upon fresh patient samples taken directly from the operating room for analysis across multiple platforms: IHC, single cell expression profiling, and spatial transcriptomics. We compared tumors from patients with bone metastatic disease to tumors from patients with disease localized to the prostate. Our work (Cancer Cell, 2021 and Nature Communications, 2023) has consistently pointed towards dysregulated myeloid populations within the tumor microenvironment, particularly TREM2+ tumor associated macrophages (TAMs), as key drivers of disease progression. Methods: Our patient samples and murine pre-clinical models of prostate cancer highlighted several specifically upregulated molecules and pathways in TAMs. Here we focus on TAMs in vitro and in vivo using a new and genetically tractable myeloid model to interrogate the mechanistic role of key pathways, and how they may contribute to T-cell immune suppression. The ER-Hoxb8 system of conditional myeloid differentiation permitted the generation of isogenic cell lines to interrogate the roles of key molecules TREM2, MSR1, APOE, and MERTK through overexpression or CRISPR/Cas9 knockout. Results: Using a system of co-culture in vitro, we quantified the role of these proteins in suppressing T-cell proliferation and cytokine production, as well as their role in TAM differentiation and function. In vivo, these lines were co-injected subcutaneously with syngeneic RM1-BM3 tumor cells to quantify their effect on tumor growth and T-cell suppression in vivo. In addition to localized subcutaneous tumors, bone metastatic disease was established by intracardiac injection. Furthermore, established tumors were treated with TAM-directed small molecule therapy (e.g., MERTK inhibition) as well as immune checkpoint inhibition (anti-PD1) alone, and in combination. Conclusions: TAMs are immune suppressive myeloid cells that are not found in normal tissues. They are specifically recruited to tumors and highly enriched in bone metastatic disease. Transcriptomic analyses highlighted signaling pathways potentially amenable to productive therapeutic targeting. The ER-Hoxb8 system was highly effective in generating a genetically tractable model of TAM for study in vitro and in vivo. Our work supports the hypothesis that the specific targeting of TAMs, by focusing on critical signaling pathways, can be effective in the treatment of pre-clinical models of prostate cancer. This new approach merits further study as a potential strategy for the treatment of patients with bone metastases. Citation Format: Hanyu Zhang, Shenglin Mei, Nathan E. Jeffries, Douglas M. Dahl, Chin-Lee Wu, Philip J. Saylor, David B. Sykes. Prostate cancer bone metastasis: Therapeutic targeting of tumor associated macrophages [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 103.