Author(s): Brian J Morrison 1 , Jason C Steel 1 , John C Morris [*] 2
cancer stem cell; dendritic cell; galectin-3; immunotherapy; lung cancer
Despite recent improvements in diagnosis and treatment, lung cancer remains a major public health problem. In 2013, lung cancer is expected to cause an estimated 28% of all cancer deaths in the USA, accounting for more deaths than the next four most common cancers combined  . The overall 5âyear survival rate for all patients with lung cancer is just 16%. As a result, increased understanding of the biology of this disease and improvements in treatment are greatly needed. A unique population of tumor cells in a cancer, so called 'cancer-initiating' or 'cancer stem cells' (CSCs) is thought to be responsible for tumor organization, maintenance, progression and recurrence, and contribute to resistance to therapy. The discovery and characterization of CSCs are important advancements in cancer biology that may aid treatment of lung cancer by identifying new targets for immunotherapy.
Lung cancer is a heterogenous disease even within an individual tumor. Tumor heterogeneity is thought to be a consequence of CSCs generating progeny composed of populations of short-term proliferating cells and more differentiated cells that have aberrant differentiation and additional epigenetic changes. In contrast to these 'differentiated' tumor cells, CSCs are a transformed subpopulation of cells, hypothesized to comprise 0.1-10% of all cells within the tumor, with stem cell-like characteristics. CSCs have been identified based on a set of characteristics that include: a capacity for self-renewal; the ability to give rise to differentiated progeny; tumorigenicity; and the expression of certain cell surface and functional markers  . Putative CSCs have been isolated in acute myeloid leukemia and a number of solid tumors  . Recently, a number of investigators have identified lung CSCs  .
One current hypothesis is that treatments such as radiation and chemotherapy initially debulk a cancer of 'differentiated' tumors cells, but leave behind either innately treatment-resistant CSCs, or select for the treatment-resistant cells that are responsible for recurrence of the tumor. The targeting of lung CSCs is an attractive new strategy to improve treatment. Therapies that specifically target CSCs may eliminate the cells responsible for tumor self-maintenance, ultimately leading to tumor degeneration and regression. Achieving this aim is made difficult by the heterogeneity of CSCs, and the lack of a universal marker to isolate or target these cells.
It is now recognized that the interplay between cancer and the immune system is a critical process in the progression of a tumor  . Several mechanisms may be at work in this process (often in combination) that allow tumors to attenuate host immune responses. One of these immune regulators is CTLA-4, which is expressed primarily by T-helper cells and acts by inhibiting T-cell function. Tumor cells have subverted this process to attenuate T-cell responses  . Another is the expression of PD-L1 by tumors that mediate T-cell 'exhaustion' and hyporeactivity  . Expression of immunosuppressive cytokines, such as IL-10 and TGF-[beta], by tumors or the surrounding stroma is an additional mechanism that...