The RNA binding protein RBM39 regulates alternative splicing and is targeted by the small aryl sulphonamides E7070 (indisulam) and E7820. These molecules display strong anticancer activity by acting as a molecular glue between RBM39 and the E3 ubiquitin ligase DCAF15, leading to the polyubiquitination of RBM39 and ultimately resulting in defects in RNA splicing. Ovarian high grade serous carcinoma (HGSC) is the most prevalent, as well as the most aggressive and lethal subtype of ovarian cancer. Current standard therapeutic options include cytoreductive surgery and chemotherapy, however, even patients who initially respond well to treatment are likely to develop recurrence. Ovarian HGSC tumours are highly heterogeneous lesions traditionally categorised as ‘immune-cold’ due to the low immune infiltrate observed. Given the challenges in treatment arising from the high heterogeneity and low immune infiltrate observed, as well as the frequent late-stage diagnosis of ovarian HGSC, the development of new treatment regimens is essential. Previous studies have shown that depletion of RBM39 via indisulam treatment gives rise to highly immunogenic neoepitopes capable of increasing the response to immunotherapy in murine models of neuroblastoma. Additionally, in house data has shown that RNA-splicing derived neopeptides are expressed in ovarian cancer models in vitro. Based on this data, I hypothesise that RBM39 depletion via molecular glue indisulam modulates the tumour immune microenvironment by generating neoepitopes capable of eliciting an immune response in ovarian HGSC models.

The tumour immune microenvironment was profiled in vivo following indisulam treatment via flow cytometry and immunohistochemistry.

These results show an increase in the level of specific immune cell populations including conventional dendritic cells or tissue resident macrophages. An increase in the levels of conventional dendritic cells (cDCs), a type of antigen-presenting cell, as well as macrophages, could suggest an increase in immune activation as well as tumour immunogenicity potentially due to the presence of novel immunogenic neoepitopes.

An increase in antigen-presenting cells (APCs) such as cDCs may reflect a rise in neoantigens available for identification, aligning with our hypothesis. Overall, these results could suggest a complex immunomodulatory effect following RBM39 depletion, which could potentially benefit patients receiving immunotherapies.