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. First-line therapy for SCLC patients is a platinum-based agent and topoisomerase inhibitor. While most patients initially respond to treatment, resistance rapidly develops leading to low 5-year survival rates of less than 7%. Critically, treatment regimens for SCLC patients have remained largely unchanged over the last 30 years, highlighting the urgent clinical need for novel treatment modalities.
Immunotherapy has recently gained attention in lung cancer treatment. Although emerging clinical trials utilising anti-PD1/anti-CTLA4 blockade have shown partial responses, these approaches still need to be explored with other therapies to efficiently treat recalcitrant SCLC. Natural killer (NK) cells are an alternative to T cell-based immunotherapies. Unlike CD8 T cells, NK cells do not require sensitisation to antigens, which are often altered on the surface of tumour cells. Interestingly, by taking advantage of a novel immune-cell gene signature, bioinformatic analysis revealed a strong correlation between high NK cell score and survival benefit in SCLC patients.
To address the role of immune subsets in SCLC we depleted mice of CD8 T or NK cells during SCLC progression. While no change in metastatic dissemination was observed following depletion of CD8 T cells, metastasis was significantly increased in mice lacking NK cells. Conversely, metastatic dissemination was limited when NK cells were activated through the inhibition of negative checkpoints. Taken together, our results indicate that enhancing NK cell responses might offer a novel immunotherapeutic approach to prevent metastatic spread in SCLC.