Difference between revisions of "Team:HZAU-China/Description"

It's important to highlight the significance our project.

1. Switch apoptosis to pyroptosis in chemical therapy
Numerous patients accept chemotherapy during their fight against cancers though there are terrible drawbacks. Chemotherapy drugs can activate caspase-3-mediated pyroptosis in normal cells while apoptosis in cancer cells, resulting in severe healthy tissue damage and inefficient tumor cure⁹. However, our designed circuit can trigger pyroptosis in cancer cells to solve this problem (Figure 2).

Figure 2. Difference between traditional approach and our approach for cancer therapy. G refers to GSDMD-N275 and E refers to GSDME.

2. Pyroptosis make tumor expose to immune system
The lysate of cell rupture during pyroptosis can destroy tumor microenvironment which is vital to tumor growth. Pyroptosis not only releases "find me" signals but also "eat me" signals¹⁰. Pyroptosis induces greater ATP release than apoptosis to attract more immune cells into tumor bed, which is one of the "find me" signals. Also, ATP can bind to purinergic P2RX7 receptors on dentritic cell (DC), activating the NLRP3/ASC/Caspase-1 inflammasome and secreting interleukin-1β (IL-1β), which is required for CD8⁺ T cells to release IFN-γ which lyse tumor cells¹¹. The "eat me" signal is the phosphatidylserine externalization which recruits macrophages to engulf the tumor cells (Figure 3).

Figure 3. Schematic diagram of immune response during pyroptosis.

3. Pyroptosis combined with antibody-dependent cellular cytotoxicity (ADCC) will become more efficient
Some monoclonal antibodies such as trastuzumab (TRAST), alemtuzumab, cetuximab and panitumumab have been utilized for both solid tumors and hematologic malignancies treatments through ADCC¹² (Figure 4). It's a special way to recruit natural killer cells (NK cells), macrophages, γδ T cells, and dendritic cells to against cancer. However, lower activity of NK cells hinders the development of this approach¹³. In our project, we give a new approach to solve this problem. IL-18 released from pyroptotic cells can stimulate NK cells proliferation and activation¹⁴. Meanwhile, pyroptosis also up-regulates intercellular cell adhesion molecule-1 (ICAM-1 or CD54) which binds to alpha integrin on the tumor cell, resulting in enhancing the affinity between NK cells and tumor cells¹⁵ (Figure 5).

Figure 4. Schematic diagram of antibody-dependent cellular cytotoxicity.

Figure 5. Activation and proliferation of NK cells.

4. Safe utilization of the N-terminal of GSDMD
Recent studies demonstrated that the N-terminal of GSDMD performs function through binding to inositol phosphate (present in inner leaflet of cell membrane) in eukaryotic cell but cardiolipin (present in the inner and outer leaflets of cell membranes) in bacteria¹⁶. Thus, the N-terminal of GSDMD releasing from bacteria is avirulent to normal cells (because of its extracellular location to normal cells), but can attack tumor cells and redundant bacteria from inside.

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