Integrated Multi-Omics Landscape of Liver Metastases

BACKGROUND & AIMS: Lack of thorough knowledge about the complicated immune microenvironment (IM) within a variety of liver metastases (LMs) leads to inappropriate treatment and unsatisfactory prognosis. We aimed to characterize IM subtypes and investigate potential mechanisms in LMs. METHODS: Mass cytometry was applied to characterize immune landscape of a primary liver cancers and liver metastases cohort. Tran-scriptomic and whole-exome sequencing were used to explore potential mechanisms across distinct IM subtypes. Single-cell transcriptomic sequencing, multiplex fluorescent immunohis-tochemistry, cell culture, mouse model, Western blot, quanti-tative polymerase chain reaction, and immunohistochemistry were used for validation. RESULTS: Five IM subtypes were revealed in 100 LMs and 50 primary liver cancers. Patients featured terminally exhausted (IM1) or rare T-cell-inflamed (IM2 and IM3) immune characteristics showed worse outcome. Increased intratumor heterogeneity, enriched somatic TP53, KRAS, APC, and PIK3CA mutations and hyperactivated hypoxia signaling accounted for the formation of vicious subtypes. SLC2A1 promoted immune suppression and desert via increasing proportion of Spp1 thorn macrophages and their inhibi-tory interactions with T cells in liver metastatic lesions. Furthermore, SLC2A1 promoted immune escape and LM through inducing regulatory T cells, including regulatory T cells and LAG3 thorn CD4 thorn T cells in primary colorectal cancer. CONCLUSIONS: The study provided integrated multi-omics landscape of LM, uncovering potential mechanisms for vicious IM subtypes and confirming the roles of SLC2A1 in regulating tumor microenvironment remodeling in both primary tumor and LM lesions.

Automated summary

This study characterized the immune microenvironment subtypes of liver metastases and identified potential mechanisms using mass cytometry, transcriptomic and whole-exome sequencing. Five distinct immune subtypes were identified, and patients with terminally exhausted or rare T-cell-inflamed characteristics showed worse prognosis. Increased intratumor heterogeneity, somatic mutations in TP53, KRAS, APC, and PIK3CA, and hyperactivated hypoxia signaling contributed to the formation of these aggressive subtypes. SLC2A1 was found to promote immune suppression and escape in liver metastatic lesions through interaction with Spp1 thorn macrophages and regulatory T cells, and also played a role in primary colorectal cancer.