part of 79 ISSN 1479-6694 10.2217/FON.13.145 © 2014 Future Medicine Ltd Future Oncol. (2014) 10(1), 79–90 ABSTRACT: After several decades of modest results with nonspecifc immune stimulants, immunotherapy has become an exciting approach in the treatment of cancer. Although non-small-cell lung cancer has not been considered an immunogenic disease for very long, a better understanding of tumor immunology and the identifcation of new targets have led to the development of many clinical trials of immune-based therapies for this neoplasm. Promising results from many clinical trials suggest that immunotherapy could be an efective strategy in the management of advanced non-small-cell lung cancer. Further studies are required to help clinicians in the selection of patients who are more likely to beneft from immunotherapy strategies by the identifcation of biomarkers and to understand when the combination of immunotherapy with other agents should be recommended. 1 UOS Tumori Polmonari, IRCCS AOU San Martino IST – Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy 2 UOC Oncologia Medica A, IRCCS AOU San Martino IST – Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy 3 UOC Oncologia Medica B, IRCCS AOU San Martino IST – Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy 4 Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università di Genova, Italy *Author for correspondence: francesco.grossi@istge.it Role of immunotherapy in the treatment of advanced non-small-cell lung cancer REVIEW Erika Rijavec 1 , Carlo Genova 1 , Angela Alama 1 , Giulia Barletta 1 , Claudio Sini 1 , Paolo Pronzato 2 , Simona Coco 1 , Maria Giovanna Dal Bello 1 , Graziana Savarino 1 , Anna Truini 1 , Francesco Boccardo 3,4 & Francesco Grossi* 1 KEYWORDS • advanced non-small-cell lung cancer • cancer vaccine • CTLA-4 • IL-2 • immunotherapy • PD-1 • TLF • TLR9 Lung cancer is the leading cause of cancer-related death worldwide, with a 5-year survival rate of approximately 15% [1]. Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancer cases [2]. Despite recent improvements in systemic therapy, such as molecularly targeted therapies, the outcome of advanced NSCLC patients remains poor. Although lung tumors have not been considered immunogenic for very long, an increased under- standing of tumor immunology and the identifcation of new immunotherapeutic targets in lung cancer have opened the door for new interventional strategies for the treatment of NSCLC. The immune system plays an important role in carcinogenesis. Chronic infammation leads to an environment rich in neutrophils, macrophages, B and T cells (cytotoxic T cells), and many other types of infammatory cells that produce cytokines, such as interleukins and TNF- a, and enable angiogenesis and cancer cell proliferation. Tregs are CD4 + T lymphocytes with a key role in the suppression of T-cell response to foreign and self-antigens. Tregs can suppress cytotoxic T lympho- cytes (CD8 + T cells) and release immunosuppressive cytokines favoring cancer cells progression. A large number of Tregs have been found in peripheral blood and tumor microenvironments in NSCLC patients [3]. However, the immune system can also inhibit tumor progression. Indeed, the infammatory response induced by cancer cells results in the secretion of cytokines (e.g., IFN-g by T cells) that stimulate cytotoxic T cells and inhibit tumor progression [4,5]. Tumor cells can escape immune sur- veillance by means of many mechanisms. Tumor cells release mediators, such as prostaglandin E2, TGF-b, VEGF-A and adenosine, which inhibit the immune response. Cancer cells can also increase the expression of surface ligands or decrease major histocompatibility (MHC) class I, which mediates immune tolerance [6]. For reprint orders, please contact: reprints@futuremedicine.com