As members of the Colgate community know, especially in light of the recent passing of student Vic Krivitski ’12, cancer affects everyone’s life. Less apparent are the specific ways in which the immune system acts to mitigate cancer. To elucidate these mechanisms, a recent study in the Journal of Immunology investigates the role dendritic cells (DCs) play in killing cancer cells.
Cancer is a condition of uncontrolled cell growth. Not only are cancer cells good at promoting their own proliferation, but also they are proficient at avoiding the immune system. DCs are immune cells that have two characteristic functions, both of which can be thwarted in the presence of cancer (1). Typically, DCs act as antigen presenting cells (APCs), presenting antigens, pieces of pathogens, to lymphocytes to activate them. They can also secrete cytokines, signal molecules, that tell other cells to combat pathogens. Less well understood is DCs’ ability to act as killer DCs (KDCs), by directly engaging pathogens, and how this function is affected by cancer.
Larmonier and Bonnotte et. al. attempt to enhance the understanding of human-derived KDCs (hKDCs). KDCs have been examined previously in rats, mice, and humans (2,3,4) but this investigation provides finer details of hKDCs’ effective activation, mechanism for inducing cancer cell death, and ability to retain characteristic DC function.
hKDCs were prepared by exposing monocyte-derived DCs from cancer-free and stage IV cancer participants to low concentrations of an activating molecule, LPS. These hKDCs were found capable of killing several tumor lines (including HeLa) and reducing cancer cell viability up to 80%. This is a particularly exciting result because DCs derived from cancerous environments were found to be as effective as those from cancer free environments.
The mechanism for cancer cell death was elucidated via several experiments. ESR spectroscopy, which measures free radicals, showed that hKDCs produce reactive oxygen species (ROS). Decreased anti-tumor activity in the presence of FeTPPS, a free radical inhibitor, confirmed this result. When cancer cells and hKDCs were separated by a semi-permeable membrane, decreased anti-tumor behavior was observed suggesting that hKDCs kill cancer cells via direct cell-cell contact. Additionally, a staining experiment that allowed visualization of the dying cells as well as the death of certain apoptosis-resistant cancer cells suggests that the cells die by necrosis (catastrophic cell death) rather than apoptosis (programmed cell death). This, too, is promising because cancer cells are particularly adept at avoiding apoptosis, so a treatment that includes a necrotic mechanism might be effective against these cells.
Furthermore, the authors demonstrate that hKDCs retain their original DC functions: they are still able to present antigens (even those from cancer cells they kill themselves!) and produce cytokines. These promising results are not problem free and will require further study. hKDCs’ ability to kill certain non-cancerous cells requires an extensive investigation of the interactions between hKDCs and healthy cells. (It is important to note, however, that T lymphocytes were not killed by hKDCs. In fact, hKDCs produce cytokines that help T lymphocytes resist death.) Similarly, the mechanism of cell death itself is a danger to healthy cells, because necrosis releases dangerous toxins. Nevertheless, this study makes strides in understanding the relevancy of hDKCs for potential cancer treatments and may aid in the development of such treatments.
Reference: Lakomy, D., Janikashvili, N., Fraszczak, J., Trad, M., Audia, S., Samson, M., Ciudad, M., Vinit, J., Vergely, C., Caillot, D., et al. 2011. Cytotoxic dendritic cells generated from cancer patients. J. Immunol. 187(5): 2775-82.
(1) Brown, M.P., Diener, K.R., Fraser, C.K., and Hayball, J.D. 2010. Unraveling the complexity of cancer immune system interplay. Expert Rev. Anticancer Ther. 10: 917.
(2) Fraszczak, J., Trad, M., Janikashvili, N., Cathelin, D., Lakomy, D., Granci, V., Morizot, A., Audia, S., Micheau, O., Lagrost, L., et al. 2010. Peroxynitrite-dependent killing of cancer cells and presentation of released tumor antigens by activated dendritic cells. J. Immunol. 184: 1876–1884.
(3) Chauvin, C., Philippeau, J. M., He ́mont, C., Hubert, F. X., Wittrant, Y., Lamoureux, F., Trinite, B., Heymann, D., Re ́dini, F., and Josien, R. 2008. Killer dendritic cells link innate and adaptive immunity against established osteosarcoma in rats. Cancer Res. 68: 9433–9440.
(4) Hill, K. S., Errington, F., Steele, L. P., Merrick, A., Morgan, R., Selby, P. J., Georgopoulos, N. T., O’Donnell, D. M., and Melcher, A.A. 2008. OK432- activated human dendritic cells kill tumor cells via CD40/CD40 ligand interactions. J. Immunol. 181: 3108–3115.