Targeting myeloid-derived suppressor cells in lung cancer

Lung cancer is the leading cause of cancer-related death in the United States and worldwide. Immune checkpoint inhibitors (ICIs) have shown durable responses and improved survival in some patients with advanced non-small cell lung cancer (NSCLC). However, nearly all patients eventually progress on these therapies, and the median survival for patients with metastatic NSCLC remains around one year. Combining immunotherapy with cytotoxic chemotherapy has shown an incremental benefit but at the cost of increased toxicity. Patients who progress on currently available immunotherapies have few effective treatment options. One significant barrier to ICI therapy efficacy is the tumor microenvironment (TME), which contains immunosuppressive cells including myeloid-derived suppressor cells (MDSCs). MDSCs represent an important tumor immune escape mechanism and play a role in the development and progression of lung cancer. Higher levels of MDSCs in the blood are associated with shorter overall survival in patients with NSCLC, and MDSCs are associated with resistance to immune checkpoint inhibitor (ICI) therapy. However, there is significant variation in methods of measurement of MDSCs including 1) the classification of the most common phenotypes, namely CD15+ polymorphonuclear MDSC (PMN-MDSC) and CD14+ monocytic MDSC (M-MDSC), and 2) the functional assessment of MDSCs. There are also significant differences in MDSC function and phenotype in animal models and in patients with cancer. We propose to investigate the role of MDSCs in tumor immune escape, and to target the immunosuppressive impact of MDSCs to improve outcomes of patients with NSCLC treated with ICI. Utilizing mass cytometry and in vitro co-culture assays, we will evaluate MDSC levels and function as well as immune cell subset changes in patients receiving standard of care immunotherapy to identify the cell populations that drive immune responses and resistance. We will then conduct a phase 1b clinical trial of all-trans retinoic acid (ATRA) combined with atezolizumab to test whether this treatment can improve responses and overcome ICI resistance in patients with NSCLC who have progressed on standard therapies. We hypothesize that a decrease in the frequency and immunosuppressive function of circulating MDSCs will be associated with increased clinical benefit in patients with NSCLC, and that modulation of MDSCs through the use of ATRA given in combination with ICIs will be safe, tolerable, and exhibit preliminary efficacy in overcoming resistance to available ICIs. The proposed studies include the first trial of this novel treatment in patients with lung cancer and will examine the potential for targeting MDSCs to overcome resistance and enhance the efficacy of immunotherapy. If successful, these studies may lead to an increased number of patients with advanced NSCLC experiencing durable responses and improved survival.