Grant: Travel Awards - Institute Community Support

Lung cancer is the leading cause of death due to cancer worldwide and there is a dire need for new treatment strategies. Lung cancer development is driven by the expression of mutant oncogenes, with EGFR and KRAS being the most frequent mutations found in lung adenocarcinoma. The immune system provides natural defense against cancer; however, cancer cells often develop the ability to evade immune detection and can manipulate the immune system to create an immune-suppressive, cancer-promoting environment. Tumour cells can achieve this by secreting cytokines that attract and recruit these immune suppressive cells to the tumour environment. Using gene expression signatures, we quantified 22 immune cell types in over 300 human lung adenocarcinomas and 100 matched normal lung tissues and identified an immune suppressive cell type, regulatory T cells (Tregs), that were increased in lung tumours compared to normal tissue even at early stages of lung cancer. We induced expression of oncogenes commonly found in lung cancer patients (mutant KRAS and mutant EGFR) in normal cells, and found that this increased production of cytokines that recruit Tregs, particularly the cytokine CCL5. We found that CCL5 production was regulated by oncogene signaling in KRAS mutant lung cancer cells. Using a genetically engineered mouse model of lung cancer that is driven by expression of the same oncogenes, we found that Tregs were increased in tumour bearing lungs, and that there was a similar increase in CCL5. Our data suggest that oncogenic signaling regulates expression of CCL5 in lung tumor cells, and that CCL5-mediated Treg recruitment to lung tumours may occur in early stages of lung tumour development. Therefore, targeted inhibition of CCL5 or oncogenic signaling may represent therapeutic strategies to block recruitment of immune suppressive Tregs by lung tumors.