Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program - be utilized for the treatment of tumors.
In order to stimulate the training of this part of the innate immune system, the scientists used beta-glucan, a long-chain sugar molecule that occurs as a natural fiber mainly in the cell walls of fungi, oats, or barley.
The immune training already became effective at the level of blood formation in the bone marrow, in the precursor cells of the neutrophil granulocytes. Based on this newly described mechanism, it is possible that novel cancer immunotherapies that improve treatment for cancer patients will be developed in the future. The scientists published their results in the renowned specialist journal Cell.
The National Center for Tumor Diseases Dresden (NCT/UCC) is a joint institution of the German Cancer Research Center (DKFZ), the University Hospital Carl Gustav Carus Dresden, Carl Gustav Carus Faculty of Medicine at TU Dresden, and the Helmholtz- Zentrum Dresden-Rossendorf (HZDR).
Tumor cells can evade the immune system in a variety of ways and in this manner nullify its protective effect. Immunotherapies aim at preventing these evasive manoeuvers and at redirecting the natural defense mechanisms in the patient's body against the cancer cells.
Modern immunotherapies rely on the specialists of our defense system, such as T cells, dendritic cells, or certain antibodies. As part of the specific immune system, these are able to recognize suitable structures on tumor or immune cells and initiate or execute a precisely tailored defense reaction.
For the first time, scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and University Medicine Dresden were now able to demonstrate that even the non-specific immune response of our body can - through special training - be weaponized against tumors.
"Based on the mechanism described, new forms of cancer immunotherapy are conceivable which could improve the chances for treatment for certain patients in the future," says Prof. Triantafyllos Chavakis, Director of the Institute of Clinical Chemistry and Laboratory Medicine (IKL) of the University Hospital Carl Gustav Carus Dresden.
Training of neutrophil granulocytes inhibits tumor growth
At the center of the described mechanism are special immune cells, so-called neutrophil granulocytes - or neutrophils for short. These form the most common subgroup of the white blood cells and are part of the innate, non-specific immune defense.
In contrast to the specific part of our immune system - which first analyses foreign structures in the body in detail and then, with a time lag, activates tailor-made defense mechanisms - the non-specific part of the body's own defense acts as a rapid response force: if pathogens enter the body or cells degenerate, it reacts very quickly and mostly stereotypically.
However, certain stimuli can also influence - or even train - the non-specific immune response. Training causes certain actors of the rapid response force to exhibit altered properties and perform their tasks better and over a longer period of time than before: the impact of the rapid response force increases.
The researchers have now been able to demonstrate for the first time that this effect, which is already known to occur in infections, can also be used against tumors.
Neutrophil granulocytes play an important role in this process. In certain tumors, they accumulate in the environment of the tumor or migrate into it. These "tumor-associated neutrophils" - located directly at the tumor - can inhibit tumor growth, but some also have tumor-promoting properties.
It is assumed that the tumor itself releases substances that turn the neutrophils into drivers of tumor growth. In experimental models, the scientists were able to partially reverse this process, which is detrimental to healing, by specially training the non-specific immune response. In order to stimulate the immune system, they used the long-chain sugar molecule (polysaccharide) beta-glucan.
This is a natural fiber found mainly in the cell walls of fungi, oats or barley. Administrating beta-glucan caused the proportion of neutrophils with tumor-inhibiting properties to increase significantly and tumor growth to decrease.
Change in blood formation ensures the long-term effect
Of particular importance in this context was proving that the reprogramming of neutrophil granulocytes already begins in the bone marrow. Here, from stem cells, various precursor cells develop and it is from these that the different blood cells emerge.
The administration of beta-glucan altered the gene activity of the myeloid precursor cells. The neutrophils later also develop from these.
"This causes the properties of the short-lived neutrophils to change in the longer term, towards activity directed against the tumor. This is because the precursor cells form neutrophils with tumor-inhibiting properties over a longer period of time," explains joint first author Lydia Kalafati from IKL and NCT/UCC.
As the next step, it would be conceivable to utilize the principle of neutrophil training in combination with already approved immunotherapies in cancer patients.
In doing so, we also want to investigate in which types of tumors the method works particularly well, in order to then use it in a very targeted manner in future."
Martin Bornhäuser, Professor, Member of the Managing Directorate of the NCT/UCC and Director , Department of Medicine I, University Hospital Dresden
Kalafati, L., et al. (2020) Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity. Cell. doi.org/10.1016/j.cell.2020.09.058.