UCLA

Lung cancer remains the most common cause of cancer death worldwide with approximately 85% of patients having non-small cell lung cancer (NSCLC). Checkpoint blockade immunotherapy has evolved the current treatment landscape with robust and durable responses in approximately 20% of patients with progressive, locally advanced, or metastatic NSCLC, as well as in treatment-na�ve advanced disease. Inefficient tumor antigen presentation, diminished T cell infiltration into tumor and LKB1-inactivating mutations contribute to the mechanisms of resistance to programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) blockade in NSCLC. One approach to overcome this immunosuppressive tumor microenvironment (TME) is to utilize in situ vaccination with gene-modified functional antigen presenting cells (APCs) to enhance tumor antigen presentation and promote tumor-specific T cell activation. Here I address two potential therapies: 1) CCL21-genetically engineered dendritic cells (CCL21-DC) and 2) CXCL9/10-genetically engineered dendritic cells (CXCL9/10-DC), which are shown to remodel the tumor immune microenvironment and promote an anti-tumor immune response. In addition, the pre-clinical studies detailed here investigate the mechanisms of how these potential therapies can potentiate checkpoint blockade immunotherapy. These preclinical models serve as a platform to enhance our understanding of the molecular mechanisms of response and resistance to immunotherapy. In addition, these studies provide insights to anti-tumor immunity mediated by in situ DC vaccination and may in turn facilitate the improvement of novel vaccine therapies. The final chapter addresses the pressing need for the development of innovative approaches to detect and intercept lung cancer at its earliest stages of development. Using spatial multiplex immunofluorescence, this chapter highlights the efforts to understand the immune landscape in the tumor microenvironment associated with early-stage lung carcinogenesis and provides further understanding of the mechanism of lung cancer evolution. Research focusing on the development of novel strategies for cancer interception prior to the progression to advanced stages will potentially lead to a paradigm shift in the treatment of lung cancer and have a major impact on clinical outcomes.