Ricerca Progetti nazionali, regionali, internazionaliNAZIONALIPRIN 2022Immunological TArgeting

Immunological TArgeting of CAncer cells through Mvs-mediated tagging

On rather early stages of the carcinogenesis process the transformed cells become “invisible” to the immune system. From this moment on, the evolution of the tumor depends essentially on the genotype of the primitive cancer cells and on their subsequent genetic drift.

The role of the immune system in blocking cancer development in its early stage has been largely underestimated due to the fact that it is possible to study only established tumors, that is, in a situation in which the immune system has already failed in its mission. Therefore, in our opinion, a clinical treatment capable of restoring the natural anti-tumor role of the immune system could prove to be the "ultimate weapon" against cancer, considering the essential failure of therapies based on anticancer drugs due to the inevitable selection of resistant cell lines. We have discovered that monocytes, a class of immune cells, are able to specifically and unidirectionally transfer a massive quantity of proteins using extracellular vesicles (EVs) as cargo. In particular, we have found that, once monocytes are activated by tumor cells, they are able to transfer them MHC-I (major histocompatibility complex). MHC-I is a protein complex essential for the acquired immune system to recognize foreign or altered molecules on the cell surface by exposing them to the cytotoxic response of CD8+ T lymphocytes. Our preliminary data, both in vitro and in vivo, show that activated monocytes are able to transfer pMHC-I (i.e. MHC-I complex bound to an antigenic peptide) to cancer cells using EVs as cargo, making tumor cells target of a “natural” CD8+ T lymphocytes cytotoxic response. In particular, we have used immunocompetent mice immunized with ovoalbumin (OVA) in a classic induced tumorigenesis experiment and, when the tumors had reached the minimum palpable size, part of them were treated injecting activated syngenic monocytes pre-loaded with OVA peptide into the tumor. Our results show much lower tumor growth rate with respect to control mice confirming the validity of our immunological treatment in mice.

The present project is aimed to refine and improve our original immunological treatment to achieve a complete eradication of solid tumors in mouse model to laying the foundations for future treatment of cancer patients. In our opinion, the improvement in the effectiveness of our treatment passes through an increase in the availability of ligand (vaccine) in the intratumor site, without which the resident monocytes/macrophages cannot tag the cancer cells for their destruction. We will pursue this goal by testing, both in vitro and in vivo, various methods that will allow to increase over time the production or availability in situ of the ligand / vaccine, in order to obtain the complete elimination of both cancer cells and their stromal component.

 

Data di avvio 18 Ottobre 2023

Data di completamento 18 Ottobre 2025

Total cost  € 129996,00

 

Progetto 2022XF829B finanziato all’interno del Bando PRIN 2022 di cui al Decreto Direttoriale n. 104 del 02/02/2022 nell’ambito del Piano Nazionale di Ripresa e Resilienza, Missione 4 – Componente 2. Dalla Ricerca all’Impresa - Investimento 1.1 Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN), finanziato dall’Unione europea – NextGenerationEU – CUP B53D23021980006