Immunotherapy has transformed the treatment of non-small cell lung cancer (NSCLC). Today, nearly all patients with stage III and stage IV disease are treated with this modality. It nearly doubles the overall survival of patients; however, most excitingly, people who do respond can remain in remission for many years. In the past, when chemotherapy was the available treatment option, less than 5% of people with advanced NSCLC were alive 5 years after they were diagnosed. With immunotherapy, as many as 30% of people are long-term survivors. While this is a significant leap in progress against this disease, 70% of people still do not derive this long-term benefit. This is because cancers can exploit a number of different mechanisms of suppressing immune responses. The approved immunotherapies are antibodies that have been engineered to bind to a proteins called immune checkpoints (PD1and CTLA-4) that are on the surface of cells of the immune system that are programed to kill tumor cells (T cells). These immune checkpoint proteins send inhibitory signals to the T cells. When the anti-PD1 and anti-CTLA-4 antibodies bind, they block these inhibitory signals. This works well as long as the T cells can recognize the tumor cells. However in many patients, tumor cells can reduce the amount of a protein called MHC class I (MHC-I) on their surface. This protein is necessary for T cells to recognize and kill the tumor cell, so without it, tumor cells are ignored by T cells. We have very recently shown that one of the ways that tumor cells reduce their surface expression of MHC-I proteins is by secreting a protein called PCSK9, which results in the destruction of MHC-I. Treating tumor cells with an antibody that can neutralize PCSK9 prevents this from happening. We therefore propose a clinical trial where we will treat patients with anti-PSCK9, so the tumor cells will no longer be ignored by T cells, and this will therefore further improve the outcomes of patients treated with anti-PD1 and anti-CTLA-4. The patients’ tumors will also be studied in detail to discover other means of further improving the effectiveness of immunotherapy in the future. If successful, this will produce the opportunity for more patients with metastatic lung cancer to be long-term survivors.