Abstract 6045: MHC II+ VEGFA+ neutrophils induce expansion of regulatory T cells and confer colorectal cancer peritoneal metastasis

Abstract Peritoneal metastasis is a fatal mode of cancer metastasis that is accompanied by extensive stromal fibrosis and poor prognosis. Increasing evidence suggests that tumor associated neutrophils (TANs) constitute a major component of tumor-infiltrating cells in many types of cancer and contribute to tumor immunity; however, how TANs are connected to adaptive immunity and clinical relevance in peritoneal metastasis remains unclear. Here, we generated and integrated single-cell RNA and spatial transcriptomes in primary tumor, adjacent normal tissues and metastases from 7 cancer types that tend to develop peritoneal metastasis (235 samples from 124 patients). Neutrophils exhibited distinct states in different tissue types. Specially, a terminally differentiated MHC II + VEGFA+ neutrophil population with antigen presenting and oncogenic phenotype termed TAN-2 portended peritoneal metastasis and could further induce mesothelium to mesenchymal transition. These fibrotic mesothelial cells exhibit higher CXCL12 levels and recruited more TAN-2 cells via CXCR4. Notably, the antigen-presenting TAN-2 could invoke expansion of regulatory T cells in an antigen-specific manner and was associated with worse survival. Importantly, in vivo TAN-2 depletion or in combination with immune checkpoint inhibitors effectively attenuates peritoneal metastasis. Taken together, we elucidate how MHC II+ VEGFA+ TANs contribute to peritoneal metastasis, provide novel insights on innate and adaptive immunity, and demonstrate new strategies to enhance cancer immunotherapy effects. Citation Format: Shuang Deng, Shaoqiu Liu, Jian Zheng. MHC II+ VEGFA+ neutrophils induce expansion of regulatory T cells and confer colorectal cancer peritoneal metastasis [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 6045.