Team:Montpellier

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ONCOLYTICS GENES

As we wanted to fight cancer we needed an oncolytic gene that we could give to our phages who would transmit it to the tumor microbiome bacteria.

      cGAS-STING pathway

After a few research we decided to focus on genes that target STING-activation. It is a pathway that links innate and adaptive immunity by stimulating antigen-presenting cells (APC) with cyclic dinucleotides (CDN). Thanks to this stimulation the bacteria are phagocyted by the APC which then produces a high quantity of type I interferons and recruits lymphocyte T in the tumor. In order to activate this pathway thanks to phages and tumor bacteria we use the gene dacA.
Its sequence is available in this section: Parts

**Figure 1: Sketch of dacA action and cGAS-STING pathway activation.**

In order to strengthen the project, we also decided to select other anti-cancer genes that act differently and are more used.

      Azurin

The first one is the gene coding for azurin. This protein enters cancer cells and forms a complex with the p53 protein, which is known to often spreadhead cancer by mutation of its coding gene. Association with azurin stabilizes p53, triggering apoptosis of the cell [2].

**Figure 2: Sketch of Azurin action and p53 pathway activation.**

      Monoclonal antibody

The second is a VHH antibody against PDL-1. VHH are single-domain nanobodies engineered from the variable domain of camelidae heavy chain antibodies - they are the smallest antibodies that can associate with cancer antigens. PDL-1 is a protein expressed at the surface of cancer cells, that inactivates T lymphocytes and helps cancer cells escape immunity. Anti-PDL-1 antibodies activate immunity and regulate cell death. [3]

**Figure 3: Sketch of VHH anti PD-L1 action and T cell activation.**

References

[1] Daniel S. Leventhal. Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity. Nature Communication (1st June 2020)
[2] Nuno Bernades et al. Bacterial protein azurin as a new candidate drug to treat untreatable breast cancer. 1st Portuguese Biomedical Engineering Meeting. (March 2011)
[3] Maria Elena Iezzi et al. Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment. Frontiers in Immunology. (19 février 2019)