Metastasized colorectal cancer is difficult to treat. Scientists at the National Center for Tumor Diseases (NCT) and the Heidelberg University Hospital in collaboration with the German Cancer Research Center (DKFZ) have now discovered that the immune system acts as an accomplice to the metastases. Macrophages, also called scavenger cells, play a vital role in this process.
Metastasized colorectal cancer is difficult to treat. Scientists at the National Center for Tumor Diseases (NCT) and the Heidelberg University Hospital in collaboration with the German Cancer Research Center (DKFZ) have now discovered that the immune system acts as an accomplice to the metastases.
Macrophages, also called scavenger cells, play a vital role in this process. The metastases in the liver influence macrophages in a way that helps tumor cells grow and spread. The reason for this is a signal pathway which is also used by the human immunodeficiency virus (HIV) as an entry point into human cells. One inhibitor is already being used therapeutically in HIV patients.
The scientists have now tested this drug in pre-clinical experiments and in a subsequent study involving 14 patients with advanced metastatic colorectal cancer. This Phase I study was funded by the Dietmar-Hopp Foundation and the promising results have just been published in Cancer Cell.
The NCT is a joint institution of the German Cancer Research Center (DKFZ), the Heidelberg University Hospital and the German Cancer Aid (Deutsch Krebshilfe).
The life expectancy of patients with non-operable metastasized colorectal cancer is about 24 months. In an advanced stage only few treatment options remain. Immunotherapeutic approaches have been fairly unsuccessful so far, although the necessary immune cells and their signaling molecules can been found around the cancer cells. Current immunotherapies are aimed at strengthening the acquired immune response, specifically activating T-cells against the tumor cells.
The scientists from Heidelberg and Hannover have now also managed to mobilize the innate part of the immune system by re-activation.
To do this, they closely examined the immune cells, particularly the macrophages from the tissue surrounding liver metastases of colorectal cancer patients. “Originally, it was assumed that the immune defense within the metastases also had an effectiveness against the tumor“, explains Dr. Niels Halama, physician and scientist at the Medical Oncology department at the NCT.
“We can now show that in colorectal cancer patients, the metastases manipulate the macrophages around them in a way that promotes cancer growth instead of fighting it.” The signal protein CCL5, which is normally involved in inflammatory process regulation as it pulls immune cells into the affected tissue, plays a major part. High concentrations of CCL5 are found in conditions such as rheumatoid arthritis, multiple sclerosis and Morbus Hodgkin. High concentrations of CCL5 and associated tumor-promoting effects have also been found in breast cancer metastases.
The scientists have shown that the T-cells close to the liver metastasis produce CCL5. In order for the protein to work, it needs to bind to its counterpart, the CCR5 receptor. This receptor is present on the cell surface of tumor cells and macrophages and induces upon activation tumor-promoting effects. The CCR5 receptor is already well known from research into HIV, because the HI virus also binds to CCR5 and penetrates the cells this way. An already registered drug blocks the surface protein CCR5 and is used therapeutically for HIV patients.
The scientists investigated the effectiveness of this HIV drug, initially in pre-clinical trials on liver metastases. The CCR5 blockage reversed the tumor-promoting effects of the macrophage in the tissue surrounding the metastasis and showed a repolarization with anti-tumoral effects. The re-programmed scavenger cells were able to destroy the cancer cells, sparing the healthy liver tissue. “The trials have improved our understanding of immune regulation in cancer. It appears that the CCL5-CCR5 axis is important for the activation of macrophages, not only in viral infections such as HIV but also in cancer”, explains Prof. Christine Falk who works at the Medical School Hannover.
Following the pre-clinical experiments, the investigators could confirm their findings in a Phase-I trial involving 14 patients and observed a regression of individual metastases. The clinical study was funded by the Dietmar Hopp Foundation with 300.000 Euros. Prof. Dirk Jäger, Medical Director at the NCT and Coordinator of the Tumor Immunology Program at DKFZ reports: “The data show that the HIV medication is very well-tolerated and the response in combination with chemotherapy is indeed very promising. “New immunotherapies could significantly improve the treatment options, especially for colorectal cancer patients“, adds Prof. Markus W. Büchler, Managing Director of the Surgical University Hospital in Heidelberg.
In this research project, macrophages were, for the first time successfully re-polarized through CCR5 inhibition with anti-tumoral effects. The scientists now hope to further develop this new immune therapy which uses the innate immune system. Niels Halama, who is also principle investigator of the colorectal cancer study adds: “Further clinical studies are in preparation that should improve our understanding of how this new therapy option could also be beneficial for the treatment of other types of tumors.”
An image for this press release is available at
Legend: The HIV drug Maraviroc blocks the surface protein CCR5. This activates the macrophages in the liver to fight the metastases. In this patient, the metastases in the liver (left) disappeared following treatment (right).
Halama N, Zoernig I, Berthel A , Kahlert C, Klupp F, Suarez-Carmona M, Suetterlin T, Brand K, Krauss J, Lasitschka F, Lerchl T, Luckner-Minden C, Ulrich A, Koch M, Weitz J, Schneider M, Buechler M W, Zitvogel L, Herrmann T, Benner A, Kunz C, Luecke S, Springfeld C, Grabe N, Falk CS, Jaeger D (2016) Tumoral immune cell exploitation in colorectal cancer liver metastases can be targeted effectively by anti-CCR5 therapy in cancer patients. Cancer Cell 29: 587-601
Dr. Friederike Fellenberg
Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg
Press and Public Relations
Im Neuenheimer Feld 460
Tel.: +49 6221 56-5930
Fax: +49 6221 56-5350
Dr. Stefanie Seltmann
Deutsches Krebsforschungszentrum (DKFZ)
Press Officer and Head of Press and Public Relations
Im Neuenheimer Feld 280
Tel.: +49 6221 42-2854
Fax: +49 6221 42-2968
Universitätsklinikum Heidelberg und Medizinische Fakultät der Universität Heidelberg
Press Officer and Head of Press and Public Relations
Im Neuenheimer Feld 672
Tel.: +49 6221 56-5052
Fax: +49 6221 56-4544
The National Center for Tumor Diseases (NCT) Heidelberg
The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center, Heidelberg University Hospital and German Cancer Aid. The NCT's goal is to link promising approaches from cancer research with patient care from diagnosis to treatment, aftercare and prevention. The interdisciplinary tumor outpatient clinic is the central element of the NCT. Here the patients benefit from an individual treatment plan prepared in a timely manner in interdisciplinary expert rounds, the so-called tumor boards. Participation in clinical studies provides access to innovative therapies. The NCT thereby acts as a pioneering platform that translates novel research results from the laboratory into clinical practice. The NCT cooperates with self-help groups and supports them in their work.
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
The German Cancer Research Center (DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.
Heidelberg University Hospital and Medical Faculty Heidelberg
Health care, research and teaching of international standing
Heidelberg University Hospital is one of the most important medical centers in Germany; Heidelberg University's Medical Faculty is one of Europe's most prestigious biomedical research facilities. Their shared objective is the development of innovative diagnostics and treatments and their prompt implementation for the benefit of the patient. The hospital and faculty employ approximately 12 600 individuals and are involved in training and qualification. Every year approximately 66 000 patients are treated as inpatients or day patients in more than 50 specialized clinical departments with about 1 900 beds, with more than 1 million patients being treated as outpatients. The Heidelberg Curriculum Medicinale (HeiCuMed) is at the forefront of medical training in Germany. At present approx. 3500 prospective physicians are studying in Heidelberg.
National Center for Tumor Diseases (NCT) Heidelberg | idw - Informationsdienst Wissenschaft
Modern genetic sequencing tools give clearer picture of how corals are related
17.08.2017 | University of Washington
The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
17.08.2017 | Physics and Astronomy
17.08.2017 | Earth Sciences
17.08.2017 | Physics and Astronomy