Optimizing innate immune signals to enhance antigen-specific adaptive responses
- Author(s): Chapon, Maxime
- Advisor(s): Cheng, Genhong
- et al.
The innate and adaptive immune responses are intertwined systems that require complex regulation to achieve an efficient protection from pathogens and diseases. Upon sensing of a foreign attack through specialized receptors, cells activate the transcription of cytokines such as type-I interferons to emit a danger signal and regulate their function. The strength and complexity of this signal is dependent on the type of pathogen recognition receptor (PRR) engaged. These signals can then skew the type of antigen-specific adaptive immune response that is created. In the past decade, there has been a renewed interest in using the immune system to fight cancer. A better understanding of how one can use the innate immune signals to trigger an efficacious adaptive immune response would help improve novel immunotherapies.
One of the tools used to trigger such immune response is oncolytic viruses, such as Herpes Simplex virus type 1 (HSV-1). HSV-1 has evolved proteins able to regulate the type-I interferon response to enhance its ability to reproduce and limit attacks from the immune system. In this work, we examine the entire HSV-1 genome to determine which genes are responsible for this phenotype and characterize a novel interferon regulating protein, UL42.
Another promising pathogen that has been used to provoke anti-tumoral responses is the bacterium Listeria monocytogenes (Lm). Lm infection leads to a strong CD8 cytotoxic T-cell response which can be retargeted towards cancerous antigens. Here, we describe how we developed a construct to express neoantigens in Lm to trigger an antigen-specific immune response. Our results indicate that this strategy was successful in vitro but did not translate in vivo, possibly because of poor expression of the construct.
The antigen-specific T-cell receptor (TCR) repertoire can vary in diversity (breath) and individual clonal characteristics such as avidity or differentiated cell type. The extent to which the innate immune response regulates the selection of the TCR repertoire in response to a specific pathogen is poorly understood. Herein, we use an in vivo mouse model to investigate how different PRR ligands can affect the selection of this repertoire. Our results suggest that ligands for distinct toll-like receptors (TLR) might contribute to the selection of different TCR variable fragment families. We did not detect any difference in the complexity of the repertoire following stimulation with different TLR ligands but suggest this might be due to technical limitations associated with our in vivo model.