Targeting the HMGB1-IL32 pathway to alleviate T cell exhaustion in epithelial ovarian cancer

Single-cell gene expression data can provide insights into cell-cell communication, enabling us to understand the interaction between cancer cells and microenvironmental cells. Here, our goal was to unravel how intercellular communication influences terminally exhausted CD8 + T cells in the ovarian tumor microenvironment. We processed and integrated ovarian cancer scRNA-Seq samples and delineated distinct cellular populations based on the expression patterns of established canonical marker genes. We performed a pseudotime trajectory analysis of CD8 + T cells and analyzed the communication of ovarian cancer cells with terminally exhausted CD8 + T cells. Investigating cell lineage and inferring pseudotimes revealed the transition of the CD8 + T cells from naïve-like to six different end-states, with central memory (35%), effector memory (31%), and terminally exhausted (25%) CD8 + T cells being the most abundant CD8 + T cell subtypes. Cell-cell communication analysis identified the HMGB1-HAVCR2 ligand-receptor pair mediating communication from ovarian cancer cells to terminally exhausted CD8 + T cells. High Mobility Group Box 1 (HMGB1) was identified as a key ligand expressed in ovarian cancer cells influencing the IL32 expression in terminally exhausted CD8 + T cells. The signaling path from HMGB1 to IL32 revealed NFKB1 as the most significant signaling mediator and TP53 as the most significant transcriptional regulator via which HMGB1 influenced IL32 expression in CD8 + T cells. The HMGB1-IL32 signaling pathway identified in our analysis can serve as a therapy target for a new generation of adjuvant therapy designed to suppress and disrupt tumor cells' influence on the microenvironment and enhance immunotherapy efficiency.