Lung cancer is the fifth most diagnosed cancer, and the leading cause of cancer-related death in Australia. Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, characterised by early metastatic spread. While most patients initially respond to platinum-based chemotherapy, resistance rapidly develops leading to low 5-year survival rates of less than 7%. Novel treatment modalities are therefore urgently required to improve the quality-of-life of SCLC patients. Immunotherapy has recently gained attention in the treatment of lung cancer. SCLC patients exhibit a poor overall response rate to immune checkpoint blockade (ICB) therapy, compared to other subtypes lung cancer., highlighting the necessity for alternative immunotherapeutic approaches. Natural killer (NK) cells are an alternative to T cell-based immunotherapies, that do not require sensitisation to antigens presented on the surface of tumour cells.
To investigate the immune microenvironment of SCLC, we analysed a published cohort RNA sequencing data from treatment naïve SCLC patients and investigated immune infiltration using established immune cell signatures. We identified that immune cell infiltration scores stratified the four subtypes of SCLC, suggesting ICB may be prognostic in some patient cohorts. To functionally evaluate the role of cytotoxic immune cells in the surveillance of SCLC dissemination, we made use of an immune-competent SCLC murine model, that faithfully mimics the human disease. SCLC cell lines generated from this model were utilised in transplantation studies to assess the role of CD8 T cells and NK cells in primary tumour growth and metastasis. Critically, these studies reveal an important role of NK cells in controlling the dissemination of SCLC cells. Conversely, metastasis was robustly controlled when NK cells were activated through the inhibition of negative checkpoints and when combined with ICB. Taken together, our results indicate that enhancing NK cell responses might offer a novel immunotherapeutic approach to control metastatic spread in SCLC.