Cellular and molecular immunology of lung cancer: therapeutic implications

Abstract

Although the incidence of lung cancer is declining, the prognosis remains poor. This is likely due to lack of early detection and only recent developments in selective cancer therapies. Key immune cells involved in the pathogenesis of lung cancer include CD4(+) T lymphocytes, macrophages, dendritic cells and NK cells. The growing understanding of these cells indicates a highly complex and intertwined network of their involvement in each stage of lung cancer. Immune cell types and numbers affect prognosis and could offer an opportunity for clinical therapeutic applications. However, an incomplete understanding of immune cell involvement and the underlying processes in lung cancer still remain. Deeper investigation focusing on the role of the immune cells will further the understanding of lung carcinogenesis and develop novel therapeutic approaches for the treatment and management of patients with more specialized and selective lung cancer.

Keywords: NK cells; Th17 cells; Treg; dendritic cells; helper T cells; immunotherapy; lung cancer; macrophages; non-small-cell lung cancer.

Figure 1. Cigarette smoke and other carcinogens promote lung cancer by inducing aberrant receptor activation, cytogenetic effects, and excess inflammation

These pathways ultimately contribute a pro-tumorigenic environment through abnormalities in the control of cellular growth, angiogenesis, and pro-survival signaling. COX2, cyclooxygenase-2; HIF, hypoxia inducible factor; STAT3, signal transducer and activator of transcription-3

Figure 2. Schema of CD4+ T cell development

Cytokine presence influences mature T cell fate and subsequent immune responses. Th1 cells elicit a generally anti-tumorigenic response by activating M1 macrophages and cytotoxic adaptive immune cells. Th2 and Treg cells have a generally pro-tumor effect. Th17 cells have a dual role in lung cancer.

Figure 3. Th17 cell subsets offer distinct roles in tumor progression

Th17 cells induced by TGF-β and IL-21 generally elicit a pro-tumor effect, whereas those induced by IL-6 and IL-23 are anti-tumorigenic due to the recruitment of cytotoxic lymphocytes (CTL) and the promotion of innate immune cells.. Levels of IL-17 and IFNγ are implicated in these opposing Th17 activities.

Figure 4. Immune cell targets of current clinical and pre-clinical immunotherapies

The complex involvement of each immune cell, whether directly or indirectly, in cancer progression offers a vast array of potential immunotherapeutic targets. Current approaches include vaccines (often targeted to specific cells), adoptive transfer of cells activated ex vivo, and immune regulatory antibodies that target specific immune signaling pathways. Details of each therapy in regards to their mechanism of action are provided in Table 2.