IP6K3 laat metabole aanpassing van nierkankercellen toe tijdens metastatische uitgroei

In the last years, immunotherapy has emerged as a promising treatment for cancer patients. Immune system-based cancer therapies offer a rapid and durable activity, mostly because, once the immune system is activated, it can potentiate a self-propagating and adaptable response. Indeed, immunotherapy leads to durable clinical responses, but only in a fraction of patients and certain tumor types. Changes in cancer cell metabolism can impair the outcome of immunotherapy treatments. Therefore, a deeper understanding of the metabolic reprogrammingthat occurs in the tumor microenvironment can lead to the identification of new biomarkers and targets for innovative cancer therapies. With the aim to identify metabolic features associated with immunotherapy resistance, the host lab performed transcriptome and metabolome profiling of three different murine cancer models (MC38 colon carcinoma, CT26 colon carcinoma, and Panc02 pancreatic ductal adenocarcinoma) treated with anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies. From the transcriptome analysis, the lab identified a pool of deregulated genes in PD-1 resistance. Among these, a gene coding for a protein that belongs to the inositol phosphokinase (IPK) family, was found to be upregulated under PD-1 treatment, suggesting that it may be involved in immunotherapy resistance. We have preliminary evidence that the knock out (KO) of this specific IPK leads to a significant reduction in tumor volume, even more evident when combining the KO with immunotherapy treatments. These results suggest that the KO of this inositol phosphokinase allows immunotherapy response in vivo. This project will further unravel the role of this IPK in cancer cells during tumor progression and potentially identify a novel approach to enable optimal immunotherapy in refractory tumors.