Okan Gultekin

High-grade serous ovarian cancer, the most common and aggressive ovarian cancer subtype, frequently metastasises to visceral adipose tissues. In these tissues, the extracellular matrix through which ovarian cancer cells migrate is constrained by the presence and preponderance of adipocytes. How cells migrate in this unique environment is not known, yet critical to understanding metastatic progression. To study these processes, we developed biomimetic organo-hydrogels that recreate structural, mechanical, and biochemical properties of human adipose tissues. We show that ovarian cancer cells present invasive tropism towards organo-hydrogels, replicating the behaviour observed in native adipose tissues. This migration is facilitated by the mechanical anisotropy and microstructure of organo-hydrogels and adipose tissues, allowing the formation of migratory tracks. These results highlight the contribution of adipocytes to tissue biophysical features as a key regulatory factor of ovarian cancer cell migration and demonstrate that organo-hydrogels are particularly relevant tools to develop in vitro models of complex tissue architectures with high cellularity.

Immune cell-based immunotherapy has emerged as a promising strategy for both hematologic malignancies and solid tumors. The adaptive properties of T and B cells, namely, antigen specificity and long-term immune memory, form the foundation of approaches such as chimeric antigen receptor (CAR) T-cell therapy and tumor vaccines. In contrast, natural killer (NK) cells, traditionally classified as innate lymphocytes, have been appreciated primarily for their immediate cytotoxicity against tumor cells, but not for long-term memory-like responses. Recent evidence has revealed a subset of NK cells defined as adaptive NK cells (aNK) capable of developing adaptive features, particularly in response to cytomegalovirus (CMV) primarily, and more recently, to ovarian tumor-derived antigens. However, whether tumor-derived peptides can specifically induce NK cell memory, and the corresponding interaction patterns, remains largely unexplored. In this study, we employed a proteogenomic approach combining RNA sequencing (RNA-seq) with HLA-E immunoprecipitation to identify both canonical and non-canonical peptides presented by primary ovarian tumor cells. Among four tumor-derived neo-antigenic peptides, the 9-mer peptide APAPAPAPL demonstrated the strongest binding affinity to HLA-E and engagement with the NK receptors NKG2C/A. Functional in vitro assays confirmed that this peptide could induce memory-like NK cell responses, including antigen-specific recall activity and enhanced tumor cytotoxicity. Furthermore, structural modeling using AutoDock Vina and Rosetta Dock illustrated that peptides with similar binding capacity shared conserved interaction patterns and docking orientations. Together, this systemic study highlights a novel mechanism for inducing NK cell memory through tumor-derived neoantigens. It also paves the way for the development of NK cell-targeted cancer vaccines, representing a new direction in tumor immunotherapy beyond conventional T cell-centered strategies.

DEGs for all myeloid cell clusters