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::

• dendritic cells
• helper T cells
• immunotherapy
• lung cancer
• macrophages
• NK cells
• non-small-cell lung cancer
• Th17 cells
• Treg

Financial & competing interests disclosure

This work was supported by research grants from the National Institutes of Health, USA to DK Agrawal. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The well-characterized Th1/Th2 cell paradigm implicates Th1 cells in a generally anti-tumorigenic response, whereas Th2 cells have a pro-tumor effect; these cells influence cancer response through cytokine release and immune cell modulation.

• Th17 cells have been very recently discovered and have a still unclear role in lung cancer; IL-23/IL-6-induced subtypes have been linked to anti-tumor activity, whereas excessive IL-17 may promote angiogenesis, tumor growth and excessive inflammation.

• Targeting Treg-mediated immune inhibition offers therapeutic potential, by utilizing Treg depletion, cytokine-induced immunomodulation or other mechanisms.

• The roles of macrophage subtypes mirror those of the Th1/Th2 paradigm in lung cancer; induced M1 macrophage polarization or inhibition of the M2 macrophage response may offer therapeutic value.

• Due to the direct effect on adaptive immunity, dendritic cells (DCs) may mediate effective anti-tumor functionality or tumor immune escape through abnormally lowered activity; DC-based immunotherapies are of particular interest, including vaccines and DC-derived exosomes, which may both be directed at particular cancer cells.

• Adoptive transfer of NK cells offers a highly selective potential therapeutic approach with minimal adverse effects; ex vivo expansion of these cells on a clinical grade large-scale is still in development.

• Cytotoxic T cells are of particular interest for immunotherapy, especially through adoptive T-cell transfer, which is performed by either ex vivo expansion of endogenous T cells (generally isolated tumor-infiltrating lymphocytes) or genetic modification (e.g., chimeric antigen receptor T cells to allow MHC independent anti-tumor activity).

• Vaccines targeting a wide array of tumor antigens are in various stages of clinical testing; some antigens targeted include MAGE, MUC-1, EGF or EGFR, HER2, CEA and WT-1.Combination therapy of vaccines in conjunction with immunomodulatory antibodies and/or chemoradiotherapies may improve treatment; the most well-characterized targets for inhibitory antibodies are CTLA-4 and PD-1.

Notes