Immunotherapy is a promising approach to treat cancer and infectious diseases, but innovative approaches are required. The cGAS-cGAMP-STING pathway can induce a potent immune response against viruses. It is also implicated in antitumoral immune responses that are effective. We have recently discovered that the small second messenger cGAMP can be packaged by viruses to stimulate immunity in target cells. We have developed methods to produce non-infectious virus-like particles containing cGAMP (cGAMP-VLPs) that strongly stimulate this innovative immune pathway. We will test the idea that cGAMP-VLPs are potent activators of anti-tumoral and anti-viral immunity. To reach this proof-of-concept, we propose pre-clinical development plan in translational mouse models.

Intercellular communication via secreted signals is essential for tissue development and homeostasis. Cytokines are small secreted proteins, originally characterized as leukocyte-derived modulators of defense responses. Growing evidence indicates that cytokines mediate essential homeostatic crosstalk between epithelial and immune cells in barrier tissues such as the intestine. Our preliminary data in zebrafish shows that most embryonic intestinal epithelial cells express cytokines, before cytokine-expressing lymphocytes are generated. In the adult intestine, cytokine production by the epithelial layer is reduced while maintained by adult leukocytes. The roles of embryonic, epithelial-derived cytokines remain unclear. It also is unclear whether epithelial and lymphoid sources of cytokines have similar functions. Here, we hypothesize that cytokines participate in essential aspects of epithelial biology through different and tightly controlled cytokine sources during early ontogeny and in the adult. We propose a research program at the junction of developmental biology, immunobiology and gut physiology aiming to uncover how different modes of cytokine production control embryonic development and adult epithelial homeostasis. Our specific aims are: (i) to identify changes in intestinal epithelial cell diversity and cytokine sources during normal development and upon inflammation; (ii) to analyze the role of cytokines in intestinal epithelial development; (iii) to specify the role of innate lymphoid cells, an abundant source of cytokines, in epithelial cell homeostasis; (iv) to determine the relationship between the microbiota and the cytokine-mediated control of epithelial development and homeostasis. This project will provide fundamental insights into how intercellular communication controls organogenesis and maintains tissue homeostasis.

Signaling pathways are cascades of biochemical reactions that transduce environmental signals to the cell interior. The cells rely on the information transduced through signalling pathways to govern biological functions and maximise the fitness of the organism. Conversely, defects in the signalling pathways are implicated in various diseases, e.g. carcinogenesis. The intricate network of signalling pathways indicates the existence of sophisticated information processing mechanisms, motivating the key questions of this project: How much information is transmitted from the environment through the signalling pathway? How many features of the signals are conveyed? Are signals integrated over time? To answer these questions, the project combines state of the art quantitative optogenetic experiments and theoretical modelling using information theory to quantify the information flow in the canonical MAPK signaling pathway. Experimentally, a well-defined stimulus will be applied at the beginning of the pathway while measuring the response at the end of the signaling cascade. The results will be integrated into a theoretical framework based on statistical physics and information theory to quantify how much static and dynamic information is being transmitted, offering key insights into cell function — the building blocks of living organisms — with potential application in drug design. The strong interdisciplinary nature of this project and the detailed dissemination strategy promotes collaboration between research communities of physicists and biologists, as well as reinforces information as a key concept in life sciences. The included training plan ensures the candidate will acquire skills in advanced experimental and theoretical techniques, and the two-way transfer of knowledge provides mutual benefit between the candidate and the host institution.