The study provides new strategies to improve the effectiveness of clinical T-cell therapy

The team of Deng Liufu researchers from Shanghai Institute of Immunology has revealed the mechanism by which endogenous cGAS-STING signal promotes the action mechanism of T-cell anti-tumor immune response by maintaining the "dryness" of CD8-T cells, which provides a new strategy and basis for improving the effectiveness of clinical T-cell therapy. The findings were published recently in Science-Translational Medicine.
immunotherapy is a hot topic in the field of tumor therapy, and T-cell-based immunotherapy faces multiple challenges in eradicating solid tumors. The greatest advantage of T-cell therapy is that tumor antigens can be specifically identified, thus effectively killing tumor cells to prevent tumor immune escape. However, continuous antigen stimulation leads to T-cell depletion, increased surface inhibitory subjects (e.g. PD-1, etc.) and decreased effect function. Currently, depleted CD
T cell responses can be reactivated by blocking the PD-1 path, allowing "exhausted" T cells to "resuscitate with blood", but the strategy is still limited by T cell quality. Therefore, how to improve the quality of T cells to keep the T cells of immunotherapy longer, to promote their replication and amplification is a new strategy to improve the effectiveness of T-cell therapy.
cGAS (cyclic GMP-AMP synthase)-STING pathway is an important way to initiate a natural immune response to anti-tumor, and is expected to become a target for a new generation of immunotherapy that turns tumors from "cold" to "hot". At present, the research of cGAS-STING pathology mainly focuses on tumor cells and natural immune cells, and finds that it plays a very important role in tumor immunity, cell aging, inflammatory disease and viral infection, but little is known about the changes in cGAS-STING pathology in T cells, especially in tumor micro-environment.
deng Liufu team found that the external blood CD in cancer patients
The expression of cGAS and STING in T cells was significantly reduced, suggesting that cGAS and STING are important
T cells in CD cells. The mouse tumor model of T-cell retransmission was used to prove that CD
T cell cGAS and STING deficiency can weaken the effect of T-cell treatment of tumors. The researchers further used genetics, pharmacological tools, and blocking antibodies to interfere with cGAS-STING and Type I interferon signals, demonstrating that this pathway is essential for maintaining anti-tumor stem cell-like CD
T cells and optimal anti-tumor response. It was also found that cGAS and STING affected the "dryness" of depleted CD8 plus T cells in tumor micro-environment by regulating the expression of TCF1 and Slamf6. CGAS-STING-mediated type I interferon signals enhance the differentiation of stem cell-like CD
T cells in the form of self-secretion, while preventing the production of effect factors by inhibiting Akt's activity. In addition, in vivo or in vitro stimulation, genomic DNA is selectively rich in the plasma of CD
T cells, which is the key to the activity of cGAS-STING path pathlands in T cells. There are also such groups of cells in human exosymistic blood, both with the characteristics of memory cells, but also with the characteristics of stem cells, named stem cell-like memory T cells (Tscm), this group of cells proliferation capacity and anti-tumor activity in all T-cell sub-groups are the strongest. The study found that THE STING agitant diABZI-C3 promoted the differentiation of Nave T cells into Tscm substations in the outer blood of healthy volunteers and cancer patients. Even more exciting is the further application of human-based mouse models to find that STING astrists can significantly improve the efficiency of CAR-T cell therapy for A549 solid tumors.
team borrowed Sun Wukong from "The Travels of the West" to portray the findings. That is, on the way west, in order to reduce demons (tumor cells), Sun Wukong (CD
T cells) need to tighten the spell of the magic (STING) and the magic of the eye of fire (cGAS), in addition to distractions, overcome thousands of difficulties and obstacles, to obtain the truth, repair the positive results.The first authors of
's paper are Assistant Researcher Li Wenwen and Postdoctoral Lu Wei, and the communication is written by Deng Liufu, Researcher of Shanghai Institute of Immunology, Shanghai Jiaoxuan University School of Medicine, Professor Devin di Wen of Renji Hospital affiliated with Shanghai Jiaoxuan University, and Yang Zhaoming Researcher of Shanghai Jiaoxuan University. At the same time, the study was supported by Professor Cheng Jinke and Professor Su Bing of Shanghai Jiaotong University School of Medicine, Professor Fu Yang heart of UT South Medical Center, Professor Gobo of Tongji University and Researcher Wang Shengsheng of the
Institute of Biophysics. (Source: Li Wenwen, China Science Journal, Lu Xin)
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