Generation of novel therapeutic approaches to selectively target senescent cells in prostate cancer

Prostate cancer is the second commonest malignancy in men worldwide and the sixth most typical cause of male mortality1. Patients with metastatic prostate cancer, specifically those with disease progression following primary androgen ablation therapy, are considered refractory to hormonal therapy. The treatment of castration-resistant prostate cancer (CRPC) remains unsatisfactory, and, unfortunately, chemotherapy can only marginally improve patient survival, providing a palliative benefit in this setting.2,3 Besides, immune checkpoint inhibitors and immunotherapies have shown poor efficacy and no increase in overall survival outcomes.4 Hence, there is an urgent need to develop novel effective targeted therapies to enhance the treatment of patients with androgen-resistant diseases. This project aims to identify novel immune checkpoints in prostate cancer and their exploitation as a novel target for developing drug delivery systems and immunotherapeutic strategies. Starting from bulk-RNA and single-cell data from human patients, we identified a transmembrane protein, Nectin2, upregulated in epithelial prostate cancer cells. Nectin2 plays immunomodulatory functions, as it can interact with receptors expressed by T and NK cells. Upregulation of Nectin2 by cancer cells was found to be even higher upon senescence induction in different in vitro and in vivo models of therapy-induced senescence (TIS) and PTEN-loss-induced cellular senescence (PICS). In cancer, senescence plays both positive and negative roles. On the one hand, senescence inhibits cell growth slowing down tumor development and progression. On the other, the presence and persistence of senescent cells in the tumour may also play tumour-promoting effects such as mitogenic, antiapoptotic and angiogenic activities, mainly through their secreted factors. For this reason, the elimination of senescent cells (senolytic therapy) has been proposed as a strategy to improve the efficacy of currently available chemo-radio or targeted therapy, but the current armamentarium of effective senolytics includes a few compounds with limited selectivity and high toxicity5,6. Based on our findings, Nectin2 represents an exploitable target to remove senescent cancer cells from tumor.7 Moreover, by exploiting co-culture systems, we demonstrated that Nectin2 has immunosuppressive effects on T and NK cell-mediated cytotoxicity. In our study, we also demonstrated the Nectin2 immunosuppressive role in the co-culture of cancer cells with T and NK cells-mediated cytotoxicity. Therefore, Nectin2-targeting pharmaceutical strategies may offer a double benefit: to reactivate the immune response and to eliminate senescent cells from the tumor concurrently. We generated senolytic immunoliposomes and tandem Dual CAR-T cells recognizing Nectin2 and prostate-specific membrane antigen (PSMA) to target senescent prostate tumour cells, and we confirmed their specificity and selectivity in multiple in vitro assays. Our next goal is to assess their efficacy and safety in preclinical models of prostate cancer.