Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer

Trinity J. Bivalacqua, Abramson Cancer Center, University of Pennsylvania School of Medicine, US

14 février 2022

Séminaire
Photo de Trinity J. Bivalacqua, Abramson Cancer Center, University of Pennsylvania School of Medicine, US

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In addition to its role as a TB vaccine, BCG has been shown to elicit heterologous protection against many other pathogens including viruses through a process termed trained immunity.   Despite its potential as a broadly protective vaccine, little has been done to determine if BCG-mediated trained immunity levels can be improved.  Here we re-engineer BCG to express high levels of c-di-AMP, a PAMP recognized by stimulator of interferon genes (STING).   We find that BCG overexpressing c-di-AMP elicits more potent signatures of trained immunity including higher proinflammatory cytokine responses, greater myeloid cell reprogramming toward inflammatory and activated states, and enhanced epigenetic and metabolomic changes.  In a model of bladder cancer, we also show that re-engineered BCG induces trained immunity and improved functionality.  These results indicate that trained immunity levels and antitumor efficacy may be significantly increased by modifying BCG to express higher levels of key PAMP molecules.

Invité par Molly Ingersoll

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