About the Project
Vaccination is the greatest success story of modern medicine with the WHO estimating 10 million deaths were prevented by vaccines between 2010 and 2015. Given that the global vaccine market is expected to exceed $50 billion by 2025, novel vaccine strategies
have both human and economic and societal significance. Upon vaccination, dendritic cells (DCs) process antigen into smaller fragments (antigen processing). The DCs then display these antigen fragments on the cell surface (antigen presentation) enabling interaction with T cells, which together with B cells generate the required immune response to afford long lasting immune memory and disease protection. Although much success has been achieved in developing vaccines to induce antibody responses, generating vaccines to induce T cell responses, specifically cytotoxic T cell responses against cancers, has proven problematic.
The inability to induce sufficient T cell responses by vaccination is a major roadblock to translating the ground-breaking developments which we are currently experiencing in the field of cancer immunotherapy. 24 hour rhythms (termed circadian rhythms) exist in organisms to efficiently align physiology and behaviour with the daily changes of the environment. Circadian rhythms are generated by the cells own molecular clock, generated by a collection of protein encoded feedback loops. We have made the striking discovery that the molecular clock in dendritic cells is a master regulator of antigen processing, presentation and T cell activation. Therefore we propose to harness the dendritic cell clock to enhance vaccine responses for cancer immunotherapy.
It is now well-established that a tight semi-contiguous network of dendritic cells reside in the different skin layers, called skin dendritic cells (skinDCs). We have shown that these cells have the capacity to induce robust T-cell responses and their accessibility on the skin make them an ideal target for vaccination. One particularly promising approach to targeting of these skin DCs is the use of microneedle (MN) arrays. MN painlessly pierce the epidermis, creating microscopic holes through which drugs, vaccines and other molecules can diffuse. We will employ a dissolvable microneedle skin patch to deliver antigen to skinDCs with and without a molecular clock and at specific times-of-day to determine the impact of the skinDC molecular clock on T cell responses. Once this is established we will determine if we can harness this skinDC molecular clock to enhance anti-tumour responses in vivo.
Circadian biology and treatment alignment to the optimal time of day is finally being realised as a critical factor for improving drug efficacy, and is being heralded as Medicine in the Fourth Dimension1. Concurrently, the gains made in Cancer Immunotherapy are being hindered by our inability to generate vaccines that sufficiently activate T cells. If successful, this project will allow us to unleash the full potential of the DC through harnessing circadian function to specifically enhance T cell responses for cancer treatment. This project will combine the research strengths within RCSI along with world-class international collaborations into a compelling project that spans the cutting-edge areas of circadian biology, drug delivery, tissue engineering and cancer immunotherapy.
1. Cederroth et al, Cell Metabolism, 2019. 2. Kissenpfennig et al, Immunity 2005. 3. Zaric et al, ACS Nano 2013, 4. Zaric et al,
Journal of Investigative Dermatology, 2015