"Light shines, and the tumor shrink". It may sound like a science fiction, or the way of exaggerating thing. But in fact, this is the result after careful study by researchers from the Rochester College. They applied a very novel and effective weapon—optogenetics into the field of cancer immunotherapy, effectively alleviating the immune inhibition in solid tumor micro-environment and minifying the tumor significantly.
As everyone knows, there is immune inhibition micro-environment around solid tumors, leading to poor immune therapy. Researchers at the Rochester College use light as a kind of media to help T-cell killing, giving light stimulation at specific places, which can activate the immune system and change the micro-environment immune inhibition state caused by tumor.
Why do they utilize light in tumor therapy?
Previous studies have shown that TGF beta mediated IP3 protein production, which is related to the inhibition of T cell-mediated cytotoxicity. While inhibiting the IP3 protein production can lead to decrease of Ca2+ concentration in TCR-dependent cells. So the researchers think that increasing the concentration of Ca2+ may reduce the effect on CTL locally, and then alleviate the immune inhibition in micro-environment.
So here comes the question that how to control the intracellular Ca2+ concentration?
They had an epiphany and came up with the optogenetics methods that shine brilliantly in neuronal research.
Optogenetics was originally found out in 2005 by Prof. Edward S Boyden and Prof. Karl Deisseroth from Stanford University, they used lentiviral vectors with high speed optical switch to transfect neurons to express a natural seaweed protein ChR2 (Channelrhodopsin-2), realizing the excitatory inhibitory control of action potential and synaptic transmission.
The protein is a light sensitive cation channel protein with a 7-transmembrane structure. Its specificity is that the protein structure changes after exposure to light, which increase the cation permeability of cell membrane.
This unparalleled characteristic made channelrhodopsin an ideal tool to control Ca2+ concentration. After CTL has been transfected with the channel protein gene, and receiving the light stimulation, Ca2+ enters the intracellular spaces, and naturally relieves the inhibition of Treg.
They put this idea into practice, and verified in mice with melanoma in ears. They tied blue light emitting diode at tumor site, and inject cytotoxic T lymphocytes which were genetically engineered to express CatCh protein. The results showed, the tumor in experimental group was significantly smaller in size compared with that in control group.
The CatCh protein used in this assay is one kind of the light sensitive channel proteins. Usually, when the receptor on T cell surface recognizes antigen, it may go through a complicated process to release Ca2+ (Ca2+ releasing is from the endoplasmic reticulum and mediated by IP3). When STIM1 (Ca2+ detector) detects the reservation of Ca2+ is insufficient in endoplasmic reticulum, it will seek extracellular Ca2+ as supplement. But CatCh directly improves the Ca2+ permeability of cell membrane, raising intracellular Ca2+ concentration without taking those process.
Previously, optogenetics are mostly used for study of neural biology, but Rochester College team creatively put it for cancer immunotherapy, which provides a new way to inhibit tumor release immunity.
However, this light guided tumor immunotherapy could only reach 300μm under the skin, so it’s only applies in tumor therapy like melanoma in skin surface. If we want to make it applicable to in-depth tumor, it needs to develop a smaller and more convenient wireless equipment. More in-depth research is urgent for people to explore.
In addition, in this experiment, mouse model is Pmel-1, a common TCR tumor model. The TCR expressed by it matches antigen on tumor cell surface. This study is to prevent the inhibition mechanism mainly from Treg. But in the real situation, the targets on tumor cells are varied and complex, which makes it difficult to confirm. Only careful analysis can determine the antigens recognized by T cell on surface of tumor cells—that is Neoantigens.
Reference：
Targeted calcium influx boosts cytotoxic T lymphocyte function in the tumour microenvironment.