Immune system priming to attack cancer-ScienceDaily

A new study by an international team co-led by George Hajishengallis of the University of Pennsylvania School of Dentistry suggests that the innate immune system, which more generally responds to invaders in the body, may be an important but overlooked factor in the success of immunotherapy. Suggests that there is.

Their work published in the journal cellStimulates the production of innate immune cells, especially neutrophils, prepared to prevent or attack tumors in animal models by “training” the innate immune system with the fungal compound β-glucan. I found that.

“The focus of immunotherapy is on adaptive immunity, as checkpoint inhibitors block the interaction between cancer cells and T cells,” said Hajishengallis, co-lead author of the study. I am. “Innate immune cells, or bone marrow cells, are not considered to be of great importance, yet our study suggests that bone marrow cells can play an important role in regulating tumor behavior. I am. “

The current study is based on previous studies published in cell A multicenter team of Hajishengallis and co-workers showed that trained immunity induced by exposure to the fungal compound β-glucan can improve immune recovery after chemotherapy in a mouse model. I did.

In previous studies, researchers also found that the “memory” of the innate immune system is retained in the bone marrow in hematopoietic stem cells, which function as progenitor cells for bone marrow cells such as neutrophils, monocytes, and macrophages. Was shown.

Next, the team wanted to know more about the mechanism by which this memory was encoded. “The fact that β-glucan helps fight tumors does not necessarily mean that it was due to trained immunity,” says Hajishengallis.

To confirm its association, researchers isolated neutrophils from innate immune-trained mice by exposure to β-glucan and received β-glucan along with cells growing into melanoma tumors. Moved to no mouse. Tumor growth was significantly suppressed in animals that received cells from trained mice.

To further support this link between bone marrow progenitor cells and the quality of trained immune protection, scientists performed bone marrow transplants and untrained bone marrow cells irradiated from “trained” mice. Transferred to mice and effectively eliminated their own bone marrow.

When challenged later, mice that received bone marrow from trained mice fought tumors much better than mice that received bone marrow from untrained mice. “This is a memory of innate immunity,” said Triantafyllos Chavakis of the Dresden University of Technology. This is Hajishengallis’ long-term collaborator and co-lead author of this study.

The experiment relied on the memory of bone marrow precursors of neutrophils in trained donor mice, which were transferred to recipient mice by transplantation to give rise to neutrophils capable of killing tumors.

Researchers suggest that antitumor activity is likely due to the fact that trained neutrophils produce higher levels of reactive oxygen species, or ROS, than untrained neutrophils. I found. ROS can be harmful in certain situations, but it can be beneficial in cancer because it acts to kill tumor cells.

Upon closer examination of the bone marrow precursors in the bone marrow of trained animals, the team biased the cells into a classification known as neutrophils, especially those associated with antitumor activity, tumor-associated neutrophil type I. We have found significant changes in gene expression. (TAN1).

Further investigation revealed that these changes elicited by innate immune training cause epigenetic rewiring of bone marrow progenitor cells. This change also indicates a type I interferon signaling pathway that acts to facilitate transcription of certain genes and is likely to be a regulator of innate immunity. training. In fact, mice lacking the type I interferon receptor were unable to produce trained neutrophils.

Beta-glucan is already in clinical trials for cancer immunotherapy, but researchers say the findings suggest a new mechanism of action with new therapeutic approaches.

“This is a breakthrough concept that can be therapeutically used for human cancer immunotherapy, especially by transferring neutrophils from β-glucan-trained donors to recipient cancer patients.” Hajishengallis said.

This study was funded by the European Research Council and the National Institutes of Health (Grants DE024716, DE026152, and DE28561).