Immune metabolism Dysregulation and Efficacy of Anti-PD-1/PD-L1 agents in nonsmall cell Lung cancer

The alteration of metabolism has been recognized as one of the main hallmarks of cancer. Arising evidence has shown that not only tumor cells, but also cells of the tumor microenvironment (TME) that have undergone metabolic rewiring are closely related to malignancy progression and tumor drug resistance. In this scenario, the investigation of the immune metabolism dysregulation in the complexity of the TME is fundamental for prediction of response to immune checkpoint inhibitors (ICIs), but it is not yet enough carried out. In Non-Small Cell Lung cancer (NSCLC), immunotherapy is dramatically changing the natural history of the disease, in both advanced and earlier stages. Indeed, combination of chemo and immunotherapy as neo adjuvant treatment in resectable patients enhances the probability of gain a complete pathological response, whereas in advanced setting only a small fraction of patients can obtain a definitive cure. Approximately 60% of metastatic patients experience a progression of disease within the first 12 months of treatment, thus there is an urgent need to identify novel and more accurate biomarkers to guide patient selection. Herein, we propose to perform a comprehensive integrated metabolic analysis of the TME components (tumor cells, immune cells and cancer associated fibroblasts) in NSCLC patients receiving ICI in first-line or neoadjuvant setting and to correlate metabolic signatures with radiological or pathological responses, respectively. Since metabolism is affected by the cross-talk among the different TME components, we plan to take advantage of the digital spatial profiling to evaluate how the metabolic rewiring is dictated by cell proximity. Considering that recruitment of effective anti-tumor immunity from the periphery proves to be crucial, we will phenotypically and metabolically analyze immune cells and plasma proteins from patients, to identify novel biomarkers more likely suitable for longitudinal immune-monitoring. As preclinical models, we will employ ex vivo organotypic tissue slices and patient-derived organoids to uncover the molecular underpinnings of the newly identified metabolic alterations. Targeting metabolic-related pathways could be crucial in restoring a favourable metabolic landscape and eventually enhancing immune-response and we plan to validate in these models, the effect of novel metabolic modulators to be combined with ICI.
The ultimate goal is to identify and validate metabolic signatures able to better predict sensitivity to immunotherapies and to discover new potential therapeutic target in NSCLC patients.