Abstract Cellular plasticity enables cancer cells to acquire new biological properties and become resistant to therapy. Late-stage castration resistant prostate cancer (CRPC) present heterogenous phenotypes in response to antiandrogen therapy, which likely arise from widely plastic adenocarcinomas, but invariably renders hormonal therapy ineffective. As a consequence, CRPCs lacks effective treatment options. Although immunotherapy has shown promising results in several cancers, CRPC is largely refractory to immunotherapeutic interventions mainly due to its tumour-immune microenvironment (TIME) with low infiltration of activated anti-tumour immune cells. Understanding how cellular plasticity modulates the TIME in the context of CRPC could provide insights on how to activate anti-cancer immunity. Using immortalized human PC cell lines, we showed that the metabolic enzyme nicotinamide N-methyltransferase (NNMT), which catalyses the transfer of methyl groups from S-adenosylmethionine to nicotinamide, is upregulated in the CRPC subtypes presenting “stem cell-like features” (CRPC-SCL). As a consequence, CRPC-SCL are more sensitivity to small molecules targeting the nicotinamide-dependent enzyme nicotinamide phospho-ribosyl transferase (NAMPT). NNMT upregulation and sensitivity to NAMPT inhibition was also validated in murine prostate cancer cells isolated from prostate lobes of a Pten−/−/trp53−/− Pb-Cre4 mouse and grown in low mitogen and low hormone, stem cell-like conditions (DVL-SCM). DVL3-SCM cells generate more aggressive tumours in vivo, though the mechanistic basis of this aggressiveness is unclear. Transcriptomic analysis revealed that DVL3-SCM cells exhibit a pronounced immunological signature with enrichment of terms linked with the innate and adaptative systems, interferon and cytokine signalling and immunoregulatory interactions between lymphoid and non-lymphoid cells. Such terms may indicate a chronically inflamed, immunosuppressive tumour niche, with altered T cell activation, that favours tumour growth. Interestingly, we have demonstrated that NNMT can be secreted by cancer cells (extracellular NNMT – eNNMT) and activate TLR4-dependent NF-kB signalling in macrophages. eNNMT is secreted by immortalized human PC cells with SCL-phenotypes (PC3) and by DVL3-SCM cells, compared with their non stem cell-like counterparts (DVL3-PAR). The increased secretion of eNNMT by PC models with stem-cell like phenotypes and NNMT intracellular upregulation, suggests eNNMT as a potential novel immunomodulatory cytokine in the context of CRPC-SCL. Targeting intra and extracellular NNMT may provide a therapeutic strategy to treat CRPC patients with SCL phenotypes. Citation Format: Agata Carreira, Marianna Ciuffreda, Nathakan Thongon, Elena Cerri, Sharon Eddie, Rebecca Steele, Charles Haughey, Beatrice Ghezzi, Irene Fiorilla, Valentina Audrito, Andrea Lunardi, Toma Tebaldi, Wouter Karthaus, Alessandro Provenzani, Ian Mills. Unravel the role of extracellular NNMT (eNNMT) in the modulation of prostate cancer (PC) tumour immune microenvironment (TIME) abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr B007.
Carreira et al. (Tue,) studied this question.