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Immune cells lose inhibitions when they grow up

LMU researchers explain efficacy of immunotherapy

Munich, 04/08/2011

The innate immune system, which can detect tumor cells and induce their destruction, can be activated by the administration of short fragments of DNA called CpG oligonucleotides. This intervention is currently being tested as a possible treatment for cancer. The results obtained so far suggest that injection of CpG leads to an increase in the numbers of myeloid-derived suppressor cells (MDSCs) in the circulation. This is puzzling because MDSCs suppress immune responses and would be expected to inhibit an effective attack on tumor cells. A group of researchers led by Privatdozentin Dr. Carole Bourquin of the Division of Clinical Pharmacology at LMU Munich University Hospital have now shown in a mouse model system that CpG actually sets off a maturation process in MDSCs, which is accompanied by the loss of their immunosuppressive activity. Thus the fact that CpG expands the population of MDSCs turns out to be irrelevant for the therapeutic effect of the treatment, because the maturation process makes these otherwise inhibitory cells immunologically ineffective. Treatment with CpG might even enhance the potency of other immunotherapies. “Our finding is of paramount importance with respect to the possible therapeutic use of CpG oligonucleotides,” says Bourquin. Her team’s next goal is to develop such an immunotherapy for tumors of the gastrointestinal tract.

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)
doi: 10.1158/1078-0432.CCR-10-2672

Priv. Doz. Dr. Carole Bourquin
Division of Clinical Pharmacology
Phone: +49 (0) 89 / 5160 – 7331

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