New discovery may turn T cells into "cybertan fighters"
◎Our reporter Zhang Jiaxing
T cells are the "warriors" of the immune system, responsible for killing tumor cells, but they are also tired.
Depletion of T cells incapacitates them.
Is it possible to make T cells a tireless "cybertan warrior"?
On January 11, the journal Nature Immunity published the latest research results of Huang Bo's team at the Institute of Basic Medicine of the Chinese Academy of Medical Sciences. They found that the cytokine interleukin 2 (interleukin-2), which was once considered a key signal for the proliferation and growth of T cells, was published. IL-2), if the timing is wrong, it can make T cells feel tired.
Further animal experiments have shown that if timely "take action" to block the mass production of interleukin 2, it is expected that immune T cells will become "cybertan fighters."
Start with the tumor microenvironment and find abnormalities
When a person feels so tired and his arm is sore that he can't lift it up, it is the accumulation of lactic acid in the muscle.
When T cells shout "tired" and are exhausted in tumor tissues, letting cancer cells go, what causes it?
Find the key factors and start with the tumor microenvironment.
However, in the signal of the tumor microenvironment, there is no new factor that accompanies the exhaustion of T cells, that is to say, there is no obvious "lactic acid accumulation".
"In the beginning we tried a lot of factors, including the well-known cytokines." The author of the paper told a reporter from Science and Technology Daily that they were also puzzled at the beginning of the study. The cytokine signals received by T cells in the tumor microenvironment are almost the same. , But will give different responses.
What makes T cells feel "tired"?
In a different way of thinking, the research team analyzed the largest amount of cytokines in advanced cancer tissues from the effect.
"In people's impression, the appearance of interleukin 2 is related to growth and proliferation, giving people a feeling of positive energy." The author of the paper said, but it appears unusually in the late stage, and other cytokines are relatively small.
This abnormality inspired the research team. In subsequent cell experiments, they confirmed their guess: the abnormally high expression of interleukin 2 did make T cells "exhausted".
In human tumor tissues, the team also confirmed this point. Tumor specimens from patients with advanced tumors expressed high levels of interleukin-2.
Follow the vine, explore the mechanism
Who produces the highly expressed interleukin 2?
"We found that the sources of interleukin-2 in the early and late stages are not the same type of T cells." The author of the paper said that the source of "Xiao He" is different.
The early cytokines belonged to the "self-produced and self-sold" type, CD8 T cells (a type of immune cell) released the factors for their own use, and later they were "produced and sold by others"-Huang Bo's team found that the tumor site caused T The cell-depleted IL-2 mainly comes from CD4 T cells.
This T cell enters the tumor in the middle and late stages of the tumor, and it participates in the exhaustion mechanism, once again showing the complexity of the body's immune system and the duality of Yin and Yang.
When a large amount of interleukin 2 produced by "other people" came "overwhelmingly", there was no balanced inhibitory mechanism, so another pathway inside the T cell was opened.
Interleukin 2 induces the massive synthesis of tryptophan hydroxylase 1 in CD8 T cells. This enzyme catalyzes the production of hydroxytryptophan from tryptophan. Hydroxytryptophan binds to the aromatic hydrocarbon receptor (AhR) and promotes its nuclear entry. Up-regulate the expression of immunosuppressive receptors, thereby inducing T cell depletion.
Blocking in time to continue to inject power into the T cell "warrior"
"We conducted in vivo experiments in mice with tumors. By adding small molecules that block interleukin 2, we can find that for early mice, if interleukin 2 is blocked, the tumor will become larger; and if it is late mice , Do the same operation, the tumor will become smaller." The author of the paper said.
In human tumor tissues, the team investigated the sources of cytokines, separated different T cell types through flow analysis, and found that CD4 T cells in advanced human tumors "take over" the important work of interleukin-2 release.
There have been many successful cases of immunotherapy, but "recurrence" has become one of the key problems.
"This is mainly because the T cell'warriors' introduced by people have entered a state of exhaustion in the later stage." The author of the paper said, "and our job is to continue to inject power into the T cells."
The team analyzed that in the pathway of T cell failure, there is a key aromatic hydrocarbon receptor. The competitive blockade of such receptors will hopefully promote the continuous secretion of functional killer factors by T cells, which will become a possibility. Therapeutic target, helping T cells to restore their previous ability to kill tumor cells is a key point to improve clinical tumor immunotherapy.
According to reports, this work was funded by the Basic Science Project of the National Natural Science Foundation of China and the Medical and Health Technology Innovation Project of the Chinese Academy of Medical Sciences.