A Malignant Subpopulation of H2AFZ+ Cells Interacts with Myeloid Cells to Promote an Anti-inflammatory Microenvironment and Drive Hepatic Metastasis, Revealing an Immunotherapeutic Strategy for Pancreatic Ductal Adenocarcinoma.

purposeHepatic metastasis (HM) is the leading cause of death in pancreatic ductal adenocarcinoma (PDAC). However, the underlying cellular and molecular programs remain poorly understood, leading to limited therapeutics for this disease. EXPERIMENTAL

designIn this study, we integrated single-cell RNA sequencing data from paired primary tumors and HMs, along with bulk RNA sequencing and IHC data from hundreds of patients to elucidate metastasis-associated programs.

resultsOur analysis identified a metastasis-prone malignant subpopulation, which is associated with a higher risk of HM and a transitional plastic state. This malignant subpopulation represents a poorly differentiated and highly proliferative phenotype, with H2AFZ potentially contributing to this phenomenon. Moreover, the presence of tumor cells in the liver was accompanied by an increased abundance of M2 macrophages, regulatory T cells, and exhausted T cells (Tex) in HMs compared with adjacent tissues, indicative of a shift toward an immunosuppressive environment. Notably, within the tumor environment of HMs, Tex exhibited elevated expression of PDCD1 and LAG3. The combined therapy targeting these two genes effectively inhibited tumor growth in mouse models of metastatic PDAC.

conclusionsIn conclusion, we reveal a metastasis-associated malignant subpopulation and provide a promising therapeutic strategy for metastatic PDAC.