Immune cells lose inhibitions when they grow up
The primary function of the immune system is to recognize foreign intruders such as infectious pathogens, and alarm the body’s cellular defenses so that an effective counterattack can be mounted against the invaders. But the system is also able to recognize and eliminate cells that have undergone malignant transformation. Immunotherapies take advantage of this ability, and are designed to support and enhance immune responses directed against tumor cells. In the new study, the researchers investigated one of these approaches, which uses short fragments of DNA called CpG oligonucleotides that are recognized by the innate immune system to activate an immune response to tumors.
Tumor cells are wily adversaries and can escape the attentions of the immune system in two ways -- by evading detection or by blocking the destructive reactions that would normally ensue following their detection by the immune surveillance system. So-called immunosuppressive cells play an important role in the latter process, and much of the research on the phenomenon has focused on myeloid-derived suppressor cells (MDSCs). “The term refers to a heterogeneous group of immature immune cells that originate in the bone marrow and are found in markedly increased numbers in the bloodstream of cancer patients and in tumor tissue,” explains Bourquin.
In cancer patients MDSCs facilitate continued growth of tumors by actively blocking their elimination by other immune cells. The form of CpG therapy studied by Bourquin has been shown to be effective in preliminary work on mice, despite the fact that the numbers of MDSCs remained high. Indeed, a recent report found that administration of CpG to tumor-free mice raised the level of MDSCs in the circulation. “This, of course, is not what one would want a cancer therapy to do, and that is why it was essential to find out how CpG therapy affects the activity of the MDSCs,” says Bourquin.
In the new study, her team was able to show that, in models of gastrointestinal tumors, treatment with CpG promotes maturation and differentiation of MDSCs. Furthermore and most importantly, this is accompanied by the loss of their immunosuppressive characteristics. Activation of differentiation is mediated by the cytokine (signal molecule) interferon alpha, which is produced by immune cells in response to exposure to CpG. The finding was confirmed by demonstrating that injection of synthetic interferon alpha alone also reduced the suppressive effects of MDSCs on immune responses. “This last result is important for future attempts to develop effective immunotherapies against cancer,” says Bourquin, who now plans to concentrate on improving the efficacy of the intervention in the treatment of tumors of the gastrointestinal tract.
The project was carried out under the auspices of the Center for Integrated Protein Science Munich (CIPSM) and was also supported by the award of an LMUexcellent Research Professorship to Dr. Stefan Endres, one of the authors of the new study. (göd/PH)
"CpG Blocks Immunosuppression by Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice"
C. Zoglmeier, H. Bauer, D. Nörenberg, G. Wedekind, P. Bittner, N. Sandholzer, M. Rapp, D. Anz, S. Endres, C. Bourquin
Clinical Cancer Research 17(7): 1-11 (2011)
Priv. Doz. Dr. Carole Bourquin
Division of Clinical Pharmacology
Phone: +49 (0) 89 / 5160 – 7331