Abstract 6553: Targeting macrophages and regulatory T cells improves response to chemotherapy in high-grade serous ovarian cancer
Authors: Samar Elorbany, Chiara Berlato, Larissa Carnevalli, Simon Barry, Eleni Maniati, Jun Wang, Ranjit Manchanda, Julia Kzhyshkowska, Frances Balkwill
Journal: Cancer Research (2024)

Abstract Despite the initial response to chemotherapy, most high-grade serous ovarian cancer (HGSOC) patients will suffer disease relapse within two years of diagnosis with no currently successful immunotherapy options.We performed single-cell RNA sequencing (scRNAseq) on omental metastasis from HGSOC patients. Analysis of 64,097 immune cells showed that neoadjuvant chemotherapy (NACT) induced immunosuppressive mechanisms that counteracted its potentially positive effects. We showed that while NACT enhanced phagocytosis and antigen presentation, this was counterbalanced by upregulation of Stabilin1 (STAB1) in eight out of eleven macrophage subpopulations we identified. The NACT associated increase in macrophage STAB1 expression was validated in a separate cohort of eighty HGSOC patients at the protein level. STAB1 is a macrophage scavenger receptor that transports phagocytosed targets to undergo significant lysosomal degradation reducing the efficiency of antigen presentation. In vitro anti-stabilin1 antibody (anti-stab1 ab) -treated macrophages had significantly reduced antigen degradation and higher CD11C expression than isotype-treated ones. Furthermore, T cells co-cultured with anti-stab1 ab -treated macrophages had increased T cell proliferation and killing.We identified thirteen CD4 subpopulations by scRNAseq, five of which were Tregs. We showed that NACT significantly upregulated and activated Tregs. Tregs displayed a shared developmental trajectory with naïve and effector T cells suggesting that those are induced rather than natural Tregs. This was supported by TCR clonal sharing between Tregs and other effector cells. In vitro T cells treated with FOXP3 anti-sense oligonucleotide (ASO), AZD8701, had an anti-tumor cytokine profile and enhanced tumor cell killing. Analysis of 69,781 scRNAseq cells from control and chemotherapy-treated HGSOC syngeneic mouse model showed similar responses. In two HGSOC syngeneic mouse models (HGS2 and 30200), combinations of chemotherapy with anti-stab1 ab and/or Foxp3-ASO significantly increased median survival of mice with established peritoneal disease compared to chemotherapy alone. Bulk RNAseq of tumors treated with anti-stab1 ab were enriched with CXCL9 positive macrophages, while Foxp3-ASO treatment showed significant increase in T helper cell infiltration and activation. Potentially cured long-term survivors (300 days+) were resistant to tumor rechallenge.In a third HGSOC mouse model (60577), in which tumors relapsed after a good initial response to chemotherapy, combinations of chemotherapy with anti-stab1 ab and/or Foxp3-ASO significantly increased the post relapse survival compared to chemotherapy alone.We believe that modulating Tregs and STAB1 could improve response to chemotherapy and can have translational potential as each AZD8701 and a humanized anti-stab1 ab are in phase I clinical trials. Citation Format: Samar Elorbany, Chiara Berlato, Larissa Carnevalli, Simon Barry, Eleni Maniati, Jun Wang, Ranjit Manchanda, Julia Kzhyshkowska, Frances Balkwill. Targeting macrophages and regulatory T cells improves response to chemotherapy in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6553.