The Immune Response to Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is responsible for more deaths worldwide than any other cancer. Currently, 5-year survival for patients with stage IA disease is just 67%. Chemotherapy offers no cure at present for patients with NSCLC. It is now recognised that the immune system plays a significant role in both tumour modulation and progression. Therefore, a better understanding of immune responses to NSCLC may lead to the development of novel therapies. In these studies, I have investigated, using immunohistochemistry, the microlocalisation of macrophage and mast cell phenotypes (as well as mast cell degranulation), TNFα expression, non-macrophage expression of markers associated with macrophage phenotypes, chemokine receptors and markers of apoptosis and cellular proliferation in surgically resected NSCLC tissue. These studies have demonstrated for the first time in NSCLC that there are two major macrophage phenotypes, M1 and M2, and that the cytotoxic M1 phenotype predominates in the islets of patients with extended survival. The presence of high numbers of mast cells in the islets, irrespective of phenotype, also predicts extended survival. In addition, TNFα expression in tumour islets was found to be an independent predictor of increased survival but its expression in tumour stroma was an independent predictor of poor survival. Also, patients with increased tumour islet expression of markers associated with cytotoxic macrophages (HLA-DR, iNOS, MRP 8/14 and TNFα) by non-macrophage cells was associated with extended survival. Patients with increased expression of CXCR3 and CCR1 in their tumour islets also had extended survival suggesting that these chemokine receptors may be involved in a pathway attracting cytotoxic components of the immune system into tumour islets. In summary, these studies highlight the importance of microlocalisation and phenotype of immune cells in determining whether they play a pro- or anti-tumorigenic role in NSCLC.