scRNAseq of HGSOC samples after neoadjuvant chemotherapy (NACT) revealed upregulation of Foxp3+ Tregs and stabilin-1+ (STAB1; a phagocytic scavenger receptor) macrophages, which were confirmed via IHC, and negatively correlated with PFS/OS. In vitro, anti-STAB1 Ab delayed antigen degradation in macrophages, and induced soluble factors that enhanced T cell cytotoxicity, while a Foxp3 antisense oligonucleotides (ASO) reduced Treg abundance and CD4+/CD8+ T cell exhaustion. In an HGS2 model with similar immune populations to human samples post-NACT, treatment with anti-STAB1 Ab, Foxp3-ASO, or both improved survival and protected the majority of mice from rechallenge.
Contributed by Morgan Janes
ABSTRACT: Single-cell RNA sequencing (scRNAseq) of tumour-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies reveals potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identifies NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs that is confirmed at the protein level. STAB1 inhibition in vitro induces anti-tumour macrophages. FOXP3 anti-sense oligonucleotide (FOXP3-ASO), repolarises Tregs to an effector T cell phenotype. ScRNAseq on 69,781 cells from an HGSOC syngeneic mouse model recapitulates the patients' data. Combining chemotherapy with anti-stabilin1 antibody and/or Foxp3-ASO significantly increases survival of mice with established peritoneal disease in two HGSOC syngeneic models and progression-free survival in a third model. Long-term survivors (300 days + ) are resistant to tumour rechallenge. Anti-stabilin1 antibody enriches the tumours with CXCL9+ macrophages and Foxp3-ASO increases TBET cell infiltration. Our results suggest that targeting these molecules in immune cells may improve chemotherapy response in patients.
Author Info: (1) Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK. s.elorbany@qmul.ac.uk. (2) Barts Cancer Institute, Queen Mary University of London, Ch
Author Info: (1) Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK. s.elorbany@qmul.ac.uk. (2) Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK. (3) Bioscience, Early Oncology, AstraZeneca, Cambridge, UK. (4) Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK. (5) Bioscience, Early Oncology, AstraZeneca, Cambridge, UK. (6) Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK. (7) Wolfson Institute of Population Health, Queen Mary University of London, London, UK. Department of Gynaecological Oncology, Barts Health NHS Trust, London, UK. (8) Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunosciences (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. German Red Cross Blood Service Baden-Wrttemberg-Hessen, Mannheim, Germany. (9) Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK.
