Reprogramming the tumor microenvironment with c-MYC-based gene circuit platform to enhance specific cancer...

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Intratumor heterogeneity (ITH) poses a significant challenge in cancer immunotherapy, impacting anti-tumoral immune responses.
• Cellular MYC (c-MYC) plays a crucial role in orchestrating ITH progression, making it a key target for therapeutic strategies.

Purpose of the Study:

• To develop a novel therapeutic platform that overcomes ITH by targeting aberrant c-MYC levels.
• To engineer a system capable of augmenting cell-to-cell communication within tumors to ensure comprehensive cancer cell targeting.
• To enhance cancer immunotherapy by reprogramming tumor cells to stimulate an anti-tumoral immune response.

Main Methods:

• Development of a c-MYC-based sensing circuit (cMSC) activated by aberrant c-MYC levels.
• Implementation of an exosome-based cell-to-cell (CtC) system to enhance communication and targeting of all tumor cells.
• Reprogramming cancer cells to express immunostimulatory agents to remodel the tumor microenvironment.

Main Results:

• The cMSC/CtC platform successfully senses aberrant c-MYC expression in cancer cells.
• The engineered system effectively targets all cells within tumors, circumventing limitations imposed by ITH.
• Expression of immunostimulatory agents led to enhanced T-cell-mediated oncolysis and remodeled the tumor microenvironment.

Conclusions:

• The developed cMSC/CtC platform offers a promising strategy for cancer immunotherapy by precisely sensing c-MYC.
• This approach effectively overcomes the challenges posed by ITH, leading to a robust immunotherapeutic response.
• Targeting aberrant c-MYC levels presents a viable avenue for developing more effective cancer treatments.