*For medical professionals only
T cells fight tumors, one is afraid that T cells will not be able to enter, the second is afraid that the T cells that come in will not work, and the third is afraid that the working T cells will be exhausted. Unfortunately, CD8+ T cells are not only depleted when they come into contact with the tumor, but also at a rapid rate......
Some studies have found that CD8+ T cells seem to lose their cell orientation after depletion, and will stay in the tumor tissue for a long time, which is completely different from other studies that reported that T cells will be excreted from the tumor.
What's the truth about this, T cells, why don't you go?
Recently, a team from the University of Cambridge published a paper in the journal Science Immunology, in which researchers tracked the behavior of T cells in response to tumor antigen signals, and found that the expanded CD8+ T cells were trapped directly in the tumor and depleted over time. In contrast, regulatory T cells (Tregs) are free to leave the tumor and enter the circulation.
Good guys, the signaling mechanism used by T cells to recognize tumor antigens has been used by tumors in turn.
Diagram of the title of the dissertation
The researchers designed a special reporter mouse (AgRSR) with a reporter gene mounted on a mouse T cell receptor (TCR) specific promoter and hybridized to EYFP-fluorescent mice, so that the fluorescent protein could be used to track the movement of T cells that responded to the antigen.
Reporter mouse design
The researchers injected mice with YUMMER1.7 melanoma cells, cancer cells commonly used to study CD8+ T cell responses in immunotherapy. Analysis of T cells in the tumor and spleen showed that EYFP+CD8+ T cells expressed PD-1, indicating that EYFP could identify T cells in response to tumor antigens.
Successfully track the expansion of CD8+ T cells in response to tumor antigen signaling
Subsequently, scRNA sequencing and TCR sequencing were performed on the sorted EYFP+ T cells to trace the differentiation of T cells in response to antigen signals.
From the analysis results, it can be seen that most of the EYFP+ cells from the spleen are not expanded, while most of the EYFP+ cells from the tumor are new forces that expand in response to antigenic signals.
However, the combat effectiveness of these expanded T cells is obviously not good. Clonal CD8+ T cells from tumors respond to antigens that are less cytotoxic and have higher exhaustion scores than T cells in lymphoid tissues.
The anti-tumor ability of CD8+ T cells in tumors is completely inadequate
In the human lung cancer dataset, the researchers observed that tumor-infiltrating CD8+ T cells, which were undetectable in the blood, had higher failure scores than those clonal subsets that were able to enter the bloodstream.
In mice, the researchers also observed that exhausted T cells were confined to the inside of the tumor.
Normally, effector CD8+ T cells can leave the tumor and re-enter the circulatory system, which has been confirmed by previous studies. So why don't these exhausted T cells leave the tumor?
The researchers re-analyzed the T cell components of mice and found that while CD8+ T cells were detectable in both the tumor and the lymphatic system, EYFP+ cells were almost exclusively detected in tumors.
EYFP+ cells are found only in tumors
From this point of view, the antigenic signaling system used by T cells to recognize tumors has been used by tumors and has become a label for trapping, imprisoning, and depleting CD8+ T cell clones.
Researchers believe that this may be an evolutionary mechanism for the body to balance pathogen control and survival in response to chronic infection. It's just that I didn't expect the tumor to take advantage of this loophole, and there are really a lot of tricks for tumors.
Resources:
[1]https://www.science.org/doi/10.1126/sciimmunol.ade2094
The author of this article丨 Dai Siyu