School of Medicine

Mechanisms of immunosuppression

Our group has identified the Cbl-b-Notch1 axis as a critical regulatory mechanism of immunosuppression in T cells and other immune components, during infections and in the tumor microenvironment. By dissecting the molecular mechanisms of this axis, we aim to uncover how it dampens protective immunity and contributes to disease progression.

Our goal is to target this pathway therapeutically to restore immune function in cancer and infections, and understand its regulation to fine-tune immune responses. This project bridges basic immunology with translational potential, offering a promising direction for novel immunotherapies.

Computational drug discovery for immunotherapy

We are developing dual-functional small molecules that modulate the immune system to restore host defense. These compounds are designed to simultaneously target infectious agents or cancer cells and overcome immunosuppression, offering a powerful strategy for treating complex diseases such as viral infections and cancer.

We have trained an AI-driven predictive model using experimental and literature-derived data to identify candidate molecules with dual immunomodulatory activity. We are leveraging this platform to design next-generation immunotherapeutics.

This project combines computational drug discovery, immunology, and translational pharmacology to pioneer a new class of broad-spectrum, immune-restorative therapies.

3D Organoid models 

Our lab is developing advanced organoid-based models to mimic tissue microenvironments for the study of mechanisms of immunosuppression and preclinical testing of novel immunotherapies. These 3D models provide a physiologically relevant platform to investigate how immune cells interact in complex tissue settings.

Selected publications

King, B., Huang, Z., Hewins, P., Cook, T., Mirzalieva, O., Larter, K., Wyczechowska, D., Crabtree, J., Garai, J., Li, L., Zabaleta, J., Barbier, M., Del Valle, L., Jurado, K., Miele, L. and Monticone, G. (2024) Adenosine analogs have immunomodulatory antiviral properties through the Adenosine A2A Receptor pathway, The Journal of Immunology, Volume 212, Issue 1_Supplement, Page 1299_4492, https://doi.org/10.4049/jimmunol.212.supp.1299.4492 

Monticone, G.*, Huang, Z., Hewins, P., Cook, T., Mirzalieva, O., King, B., Larter, K., Miller-Ensminger, T., Sanchez-Pino, M. D., Foster, T. P., Nichols, O. V., Ramsay, A. J., Majumder, S., Wyczechowska, D., Tauzier, D., Gravois, E., Crabtree, J. S., Garai, J., Li, L., Zabaleta, J., … Miele, L. (2024). Novel immunomodulatory properties of adenosine analogs promote their antiviral activity against SARS-CoV-2. EMBO reports, 25(8), 3547–3573. https://doi.org/10.1038/s44319-024-00189-4 

Monticone, G., Huang, Z., Csibi, F., Leit, S., Ciccone, D., Champhekar, A. S., Austin, J. E., Ucar, D. A., Hossain, F., Ibba, S. V., Boulares, A. H., Carpino, N., Xu, K., Majumder, S., Osborne, B. A., Loh, C., & Miele, L. (2022). Targeting the Cbl-b-Notch1 axis as a novel immunotherapeutic strategy to boost CD8+ T-cell responses. Frontiers in immunology, 13, 987298. https://doi.org/10.3389/fimmu.2022.987298  

Monticone, G., & Miele, L. (2021). Notch Pathway: A Journey from Notching Phenotypes to Cancer Immunotherapy. Advances in experimental medicine and biology, 1287, 201–222. https://doi.org/10.1007/978-3-030-55031-8_13 

Funding