Abstract C006: Tumor-associated macrophages drive prostate cancer progression via IL-1β signaling

Abstract

Abstract Inflammation is linked to prostate cancer progression. Inflammatory cell infiltrates are commonly observed in prostate biopsies, and inflammation-induced lesions (proliferative inflammatory atrophy, PIA) are precursors of prostate cancer. However, the mechanism by which inflammation impacts prostate cancer progression is poorly understood. Here, we investigated the significance of inflammation on prostate cancer progression using a cMyc-driven prostate adenocarcinoma mouse model (Hi-Myc). We observed a robust tumor-associated macrophage (TAM) infiltrate early during progression of Hi-Myc tumors. Depleting TAMs led to a decrease in both tumor weight and invasive area, demonstrating the functional importance of TAMs in tumor maintenance. To elucidate the molecular basis of how TAMs influence tumor progression, we collected Hi-Myc tumors throughout cancer development from the precursor stage of prostatic intraepithelial neoplasia to prostate adenocarcinoma and performed single-cell RNA sequencing (scRNA-seq). Our study revealed that a gene signature of strong IL-1β signaling activation was observed in TAMs from Hi-Myc tumors, but not in macrophages from wild-type prostates. Importantly, IL-1β neutralization led to delayed tumor progression with reduced tumor weight and invasive area. Furthermore, blocking IL-1β signaling decreased TAM infiltration, suggesting a positive feedback loop created by TAMs. To understand the effect of IL-1β on cancer cell invasion, we used a protease-dependent fluorescent probe to investigate the activity of major extracellular matrix degraders and found that IL-1β neutralization impairs MMP activity, likely through loss of expression by tumor cells and macrophages. To further investigate the targets of IL-1β signaling, we analyzed Il1r1 expression levels across all cell types and found the highest levels in cancer-associated fibroblasts (CAFs). Moreover, CAFs expressed elevated levels of the myeloid chemokines Ccl2, Csf1, Cxcl1, Cxcl2 as well as Il6 compared to fibroblasts from wild-type prostates. In vitro studies of wild-type prostate fibroblasts treated with recombinant IL-1β confirmed that IL-1β directly upregulates expression of these inflammatory cytokines and chemokines. In addition, IL-1β directly promotes proliferation of tumor-derived prostate cancer organoids in vitro. Overall, our study suggests that TAMs and CAFs cooperatively drive pro-tumorigenic IL-1β signaling in prostate cancer, demonstrating a direct mechanistic link between inflammation and prostate cancer progression. Citation Format: Young Sun Lee, Jimmy L. Zhao, Max Land, Joseph Chan, Perianne Smith, Roshan Sharma, Sanjay Kottapalli, Linda Fong, Zhenghao Chen, Cathy Wang, Jesse Kirkpatrick, Ava Soleimany, Samir Zaidi, Kayla Lawrence, Amanda Kulick, Teng Han, Zhen Sun, Philip Watson, Anuradha Gopalan, Ojasvi Chaudhary, Tianhao Xu, Ignas Masilionis, Ronan Chaligne, Dana Rathkopf, Michael Morris, Sangeeta Bhatia, Michael Haffner, Dana Pe'er, Charles Sawyers. Tumor-associated macrophages drive prostate cancer progression via IL-1β signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C006.