EPILUCAFS

Smoking causes chronic inflammation in the lungs, which contributes to the development of lung cancer (LuCa). This inflammation affects the immune system response and alters the immune response by affecting nearby lymph nodes and the tumour microenvironment (TME), the tissue immediately surrounding the cancer cells, which includes immune and other non-cancerous cells like fibroblast. While treatments like immune checkpoint inhibitors (ICIs) have helped us understand the immune systems role in fighting cancer, they dont work equally well for all patients. Stress and unhealthy lifestyles, which impact the immune system, may also worsen outcomes for LuCa patients by influencing gene control in the long term through epigenetic processes. In this project, we will study how chronic stress and inflammation affect cells within the TME and lymph nodes. One critical cell type for fighting cancer are T cells, but their function can be suppressed in this environment. Specifically, we will focus on the interactions of immune cells with cancer-associated fibroblasts (CAFs), which have distinct characteristics in the TME. We aim to use epigenetic drugs to restore the immune system`s ability to fight tumors. These drugs will be tested alongside ICIs to see if this combination can overcome immune suppression and improve treatment outcomes. Our approach involves: Using public RNA data and advanced techniques to create a detailed atlas of the different cells in and around lung tumors, showing how they change under stress or inflammation. Investigating how stress affects the gene regulation in CAFs and its link to T-cell dysfunction. Testing these findings using patient samples and preclinical models (in the lab and in mice). Developing and testing new treatment combinations using ICIs and epidrugs to improve patient response to therapies. Why It Matters This research will uncover how stress and inflammation contribute to immunosuppression in LuCa. By studying the epigenetic changes in tumor-associated cells, we hope to identify new drug targets that could block these harmful effects. This could lead to more effective treatments for lung cancer patients, especially those whose immune systems have been weakened by stress and other factors. The project brings together an international team of experts, each contributing unique skills, to tackle this complex challenge with an innovative and well-structured plan.