The sensing of blood nutrient availability, storage, and delivery requires robust inter-tissue crosstalk mechanisms which, for the last 70 years, we have still trying to understand in health and disease. When these mechanisms fail, metabolic pathologies such as Metabolic Syndrome (MetSy) ensue. MetSy is a complex entity that has emerged as a worldwide epidemic. The lack of knowledge of its nature, the absence of any efficient treatment, and the increasing prevalence imply a major public health concern. MetSy is defined as abdominal obesity, insulin resistance, misbalance in lipid profile, and high cardiovascular and diabetes type 2 risks. These factors, dysregulated simultaneously, suggest an underlying mechanism linking all these metabolic impairments. In 2019, I published an article proposing a novel nutrient delivery mechanism from blood to tissues based on extracellular vesicles (EVs) biology. Since then, other groups have corroborated our findings, supporting the idea that, as a complementation of the classical nutrient delivery mechanisms, EVs in circulation (cEVs) are able to deliver metabolic fuels from blood to tissues. While this new cEVs-based mechanism is occurring in healthy subjects, we don´t know if it is falling in MetSy patients, or even if it is relevant enough to alter human physiopathology. METEV aims to study these last two concepts, to address a better understanding of metabolic pathologies, in particular, the role of cEVs in the development of MetSy. My main personal objective is to learn (training) and take advantage of cutting-edge technologies to improve the knowledge of metabolic pathologies with potential relevant implications in multiple fields of medicine. This will allow forging future interdisciplinary collaborations with professionals from different areas. The present MSCA enables the development of my own collaborative network, as I will work at the Hospital La Fe (Spain), with a secondment at Aalborg University Hospital (Denmark).

Although cancer immunotherapy has achieved significant breakthroughs in recent years that has positioned it as the most promising approach to treat cancer, its overall efficacy remains limited in the majority of patients. Nutrition-deprived conditions at tumor microenvironment poses significant metabolic challenges to tumor-infiltrating lymphocytes which may contribute to failure of anti-tumor activity. The main objective of the Immunometabolomics project is to understand metabolism in CD8+ T cells, during active effector T cell development and exhaustion, using approaches that go beyond current research which have been mostly focused on glucose/energy metabolism thus disregarding the relevance of anabolic and redox reactions that are crucial in correct cellular function and proliferation. Open-ended metabolomics and metabolic flux analysis studies, in combination with genetic, nutrition and pharmacological manipulations will be employed to study areas of metabolism that have not been previously extensively studied in CD8+ T cells including 1C metabolism. The characterization of metabolism in CD8+ T cells will be gradually performed in models of higher complexity and physiological and clinical relevance from in vitro, to in vivo in genetically engineered mouse models of lung cancer and finally in lung cancer patients. Through understanding CD8+ T cell metabolism, and its modulation in cancer within tumor microenvironment, we aim to develop a basic science foundation for increasing immunotherapy efficiency in cancer through the use of complementary nutritional and/or metabolism-targeted pharmacological approaches.

Autologous immunotherapies have revolutionised cancer treatment providing impressive survival benefits in patients with blood cancers. The next generation of personalised immunotherapies using tumour-infiltrating lymphocytes (TIL) aims to overcome efficacy limitations of CAR-T therapies in the treatment of solid tumours. Lack of effective, fast, adaptive, controllable and scalable manufacturing process remains one of the critical bottlenecks for clinical adoption of such complex personalised cell therapies. In the SMARTER project, Achilles Therapeutics UK Limited, a clinical-stage company developing autologous cell therapies, partners with the centre of excellence for Cell and Gene Therapy Catapult and academic experts in process biomarker discovery (Instituto de Investigacion Sanitaria La Fe) and bioprocess sensor development (Leibniz Universitat Hannover). The consortium aims to develop a first-in-class, smart bioprocessing manufacturing platform for personalised autologous cell therapies, implementing for the first time in-line process analytical technologies and smart process control systems. The project exploits breakthrough discoveries of novel T cell expansion process biomarkers and development of new fluorescence spectroscopy sensors for real-time monitoring of critical process parameters, toa enable adaptive process control of the precision TIL biomanufacturing process. After the project, the prototype R&D platform will be ready for follow-up development of the commercial scale bioreactor in GMP environment. The SMARTER platform will critically improve production efficiency, reduce overall costs-of-goods, shorten manufacturing cycle times (shorter vein-to-vein time), decrease batch failures and lead to more consistent and predictable cell therapy product quality. Finally, the innovations will enable clinical implementation of a potential breakthrough personalised adoptive cell therapy for hardest-to-treat solid tumours such as lung cancer and melanoma.