Distinct immune features in the peritoneal cavity shape the ecosystem of gastrointestinal cancer metastasis 4693

Abstract Description Peritoneal metastasis (PM) from gastrointestinal cancers is a significant clinical challenge with no effective therapies. The peritoneal cavity is a dynamic immune environment. To identify unique peritoneal immune characteristics, we profiled peritoneal fluid from 8 colorectal cancer (CRC), 6 appendiceal PM patients, alongside 7 normal controls using single-cell RNA sequencing. In cancer patients, myeloid cells were mostly monocyte-like (VCAN+, CCR2+), with macrophages classified as LYVE1+MRC1+ macrophages or TIMD4+ mature macrophages. SPP1+ cells, previously described as tumor-promoting, were found mainly in LYVE1+MRC1+TIMD4- macrophages and LDLRhiCD36+ monocytes but were not differentially enriched between normal and tumor samples. However, cancer peritoneal fluid contained unique macrophage subsets, including LYVE1+TREM2+SPP1- macrophages, associated with endocytosis, and LYVE1-SPP1+TREM2- macrophages, predominantly found in appendiceal PM. Compared to normal controls, T cell proportions were reduced in appendiceal PM but remained similar in CRC PM. Despite this, CD8+ T cells in cancer peritoneal fluid showed robust activation profiles (TBX21, GZMB, IFNG). CD4+ T cells expressed less IFNG in cancer, and TCR clonality was negatively correlated with disease burden, measured by the peritoneal cancer index. These findings characterized the peritoneal fluid immune ecosystem in PM. The unique macrophage subsets and activated T cells offer opportunities for therapies. Funding Sources Funded by: American Surgical Association Research Award NIH/NIAID R37AI049653 NIH/NCI KOOCA264434 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)