Abstract LB195: Immunotherapies that repolarize macrophages and CD4 T cells enhance the effect of chemotherapy in high-grade serous ovarian cancer

Abstract

Abstract We asked if single-cell RNA sequencing (scRNA-seq) analysis of tumor immune cells in high-grade serous ovarian cancer (HGSOC) would reveal ways to enhance effects of neo-adjuvant chemotherapy (NACT). Analysis of 64,097 immune cells from seven HGSOC omental metastases showed that positive effects of NACT on immune responses were counterbalanced by induction of immunosuppressive mechanisms, especially related to antigen presentation and Treg activity. We identified stabilin-1 (Clever-1) on macrophages and FOXP3 in Tregs as targets and validated actions of their inhibitors in vitro. ScRNA-seq analysis of 69,781 cells from chemotherapy-treated syngeneic mouse HGSOC tumors showed significant agreement with the patient results. Combinations of chemotherapy with anti-stabilin1 antibody and/or FOXP3 inhibitor (AZD8701), FOXP3i, significantly increased median survival of mice with established peritoneal disease. Long-term survivors (300 days+) were resistant to tumor rechallenge. Analysis of bulk RNA sequencing data from treated murine tumors confirmed our hypothesis and suggested potential mechanisms to explain the anti-tumor response seen in the murine models. Tumors treated with chemotherapy plus anti-stabilin1 antibody showed significant enrichment of anti-tumor macrophage signature and antigen presentation pathway compared to chemotherapy alone. Tumors treated with chemotherapy plus FOXP3i in combination with anti-stabilin1 antibody showed significant upregulation of antigen presentation, T cell activation and cytotoxicity and T helper 1 differentiation pathways. There was significant reduction in FOXP3 positive cells and significant increase of Tbet positive cells in FOXP3i treated murine tumors suggesting repolarization of naive T cells in the tumor microenvironment towards a more anti-tumor T helper phenotype. As there are early phase clinical trials of FOXP3 inhibitor and anti-stabilin1 (Clever-1) antibody in patients with advanced cancer, these results suggest ways of improving response to chemotherapy not only in HGSOC but in other cancers that are treated by NACT. Citation Format: Samar Elorbany, Chiara Berlato, Larissa Carnevalli, Eleni Maniati, Jun Wang, Simon Barry, Ranjit Manchanda, Julia Kzhyshkowska, Frances Balkwill. Immunotherapies that repolarize macrophages and CD4 T cells enhance the effect of chemotherapy in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB195.