Abstract 770: ccRCC metastasis rewires tumor microenvironment to increase immunosuppression and fibrosis

Abstract Tumor progression and metastasis is driven by interplays between cancer cells and their surrounding tumor microenvironment (TME). Investigating the spatiotemporal transcriptomic profile of primary and metastatic tumors sheds light on how the differences in spatial architecture shape the TME and promote tumor metastasis. Here, we profiled three primary and three lung metastatic clear cell renal cell carcinoma (ccRCC) samples using the CosMx platform, which provides a 999-gene transcriptome with spatial coordinates. After cell segmentation and annotation, we further incorporate the cellular context and spatial information to identify niches by grouping the cells with similar neighboring cells. Cell-cell communication and architecture were analyzed to understand the spatial organization in primary and metastatic ccRCC. From niche analysis, 12 distinctive niches were identified, including cancer, stroma, alveolar, tertiary lymphoid structure (TLS), and mast niches, formed by 25 different cell types. Analyzing cancer niches, we found that the metastatic TME is much more immunosuppressive compared to the TME in primary ccRCC. There is a higher infiltration of exhausted T cells, Treg and M2-like macrophages in metastases. Moreover, the fibroblasts in metastases have higher expression of VEGF and metalloproteinases, which led to angiogenesis and worse prognosis. Architecture analysis showed that lung metastatic ccRCC cells, surrounded by a stromal barrier, are not directly interacting with tumor infiltrating leukocytes (TILs), whereas primary ccRCC cells interact more with TILs. Moreover, compared to the TLSs in primary ccRCC, the ones in metastases showed features of dysfunction, which was correlated with a worse prognosis. Our results show the impact of spatial architecture on primary and metastatic ccRCC, as well as the relation between spatial organization of the cellular context and cell-cell communication. In addition, it suggests that immune cells and cancer-associated fibroblasts (CAFs) are essential components of the ccRCC TME. Their interaction constitutes a major factor not only for tumor progression but also limiting therapy response in metastatic ccRCC. Citation Format: Yufei Wang, Jae-Won Cho, Yasmin Nabil Laimon, Wenxin Xu, Aseman Bagheri Sheshdeh, Nithyassree Murugan, Hsien-Chi Yuan, Jon Wee, David Braun, Toni Choueiri, Catherine Wu, Sabina Signoretti, Gordon Freeman, Martin Hemberg, Wayne Marasco. ccRCC metastasis rewires tumor microenvironment to increase immunosuppression and fibrosis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 770.