Exploring mechanisms of immunotherapy resistance in pancreatic cancer

One of the main problem of tumor treatments is the onset of the therapy resistance responsible for the progression and mortality of cancer patients. To date, cancer immunotherapy represents a new promising treatment approach but is also characterized by immune-resistance. Therapeutic regimens, such as immune checkpoint inhibitors (e.g. α- PD-1 or α-CTLA-4 antibodies), harnessing the ability of the immune system, allow to recognize and reject cancer. However, potent mechanism of immune escape include the ability of tumors to render CD8+ cytotoxic T cells present within the tumor dysfunctional (generally referred to as T cell-inflamed or “hot” tumors), the ability to exclude T cell from the tumor by exclusion mechanisms (generally referred to as non-T cell-inflamed or “cold” tumors) or more commonly a mix of both. Therefore, the main goal of our project is to identify novel mechanisms and therapeutic targets able to promote both T cell fitness and T cell influx within tumors. This will allow to overcome resistance to immune checkpoint blockade and improve clinical outcomes. The harsh tumor microenviroment (TME), along with the cellular and metabolic crosstalk between cancer and stromal cells, are key players in orchestrating these immunosuppressive mechanisms. In order to identify the gene and metabolic pathways within the TME affecting immunosuppression and resistance to immunotherapy, we set-up and performed a tailored meta-analysis. To fully appraise the key role of the identified gene in inducing immunosuppression and its therapeutic value, we will evaluate if the knockout of this gene promotes the action of the immune system and the responsiveness to immune checkpoint inhibitors in vivo. Finally, we will explore the mechanisms behind the observed phenotype. In conclusion, the aim of this study is to highlight the key role of tumor metabolism in mounting immunosuppression and to harness the tumor metabolism to increase the immune response to immunotherapy.