Immunotherapies that repolarize macrophages and regulatory T cells enhance the effect of chemotherapy in high-grade serous ovarian cancer

We conducted single-cell RNA sequencing (scRNAseq) of tumor-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies to identify potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identified NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs and these were validated at the protein level. STAB1 inhibition in vitro induced anti-tumor macrophages. FOXP3 anti-sense oligonucleotide (FOXP3-ASO), repolarised Tregs to an effector T cell phenotype. ScRNAseq on 69,781 cells from an HGSOC syngeneic mouse model recapitulated the patients' data. Combining chemotherapy with anti-stabilin1 antibody and/or Foxp3-ASO significantly increased 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+) were resistant to tumor rechallenge. Anti-stabilin1 antibody enriched the tumors with CXCL9+ macrophages and Foxp3-ASO increased TBET cell infiltration. Our results suggest targeting these molecules may improve chemotherapy response in patients. Overall design: RNA sequencing on whole omental tumors from control and treated mice, 3-4 replicates per treatment arm. The included arms are control (n=3), carboplatin and paclitaxel treated (n=3), Anti-stab1 antibody treated (n=3), carboplatin and paclitaxel plus anti-stab1 antibody (n=3), Foxp3-ASO treated (n=3), carboplatin and paclitaxel plus Foxp3-ASO(n=4), carboplatin and paclitaxel plus anti-stab1 antibody and Foxp3-ASO(n=4), Foxp3-ASO plus anti-stab1 antibody (n=3)