Ricerca Progetti nazionali, regionali, internazionaliNAZIONALIPRIN 2022Metabolic alterations and immune escape

Metabolic alterations and immune escape in colorectal cancer: "activity metabolomics" as a novel therapeutic approach

Among several mechanisms of immune tolerance, metabolic rewiring is one strategy used by cancer cells to escape the immune response. Indeed, metabolic remodeling induces changes of gene expression through epigenetic and post-transcriptional regulation and modifies tumor microenvironment, thus creating a loop which induces further metabolic alterations and/or sustains aberrant metabolism. Hence, this interplay between cancer metabolic remodeling and gene expression reprogramming sustains immune escape mechanisms. Furthermore, the metabolic crosstalk between different cell types in tumor microenvironment favors the production of metabolites, growth factors, cytokines and chemokines that directly inhibit the immune response.

Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. Immune checkpoint inhibitors (ICIs), are a new standard of care only for Microsatellite Instability High (MSI-H) metastatic CRC (mCRCs), being, conversely, inactive in the vast majority of human CRCs with MSS status. Thus, novel strategies to improve/expand ICI activity are needed.

CRC is classified into four consensus molecular subtypes (CMSs) with distinct biological features, among which the CMS1 hypermutated, frequently MSI and with higher likelihood to respond to ICIs and the CMS3 epithelial, with evident metabolic dysregulation and no responsiveness to ICIs.

The present study aims at demonstrating that the different immune phenotype between immune-responsive CMS1 and immune-resistant CMS3 cancer cells is, at least in part, due to metabolic reprogramming of cancer cells and that metabolic pathways can be targeted to improve the activity of immunotherapy in mCRCs.

Objectives:

• To identify metabolic differences between CMS1 and CMS3 tumor cells and relevant metabolites characterizing tumor microenvironment;

• To characterize molecular mechanisms underlying the above-mentioned metabolic alterations, by exploring the epigenetic and the

gene expression profile of both tumor subtypes, focusing on the enzymes and signaling mechanisms likely involved in relevant metabolic pathways;

• To explore the hypothesis that metabolic alterations may affect gene expression programs at transcriptional and/or post-transcriptional levels, thus inducing a vicious loop, which progressively worsen the immune resistance;

• To evaluate the effect of tumor metabolic modulation on immune response.

These objectives will be achieved by an “activity metabolomics” approach combined with multiomics studies, including epigenome, transcriptome and translatome evaluation, and traditional cell and molecular biology approaches and using a variety of CRC cell models.

These studies will allow us to identify: i) molecular mechanisms responsible for immune escape in CRC, ii) possible new targets for therapeutic approaches aimed at reverting immune escape mechanisms.

 

Data di avvio 18 Ottobre 2023

Data di completamento 18 Ottobre 2025

Total cost  € 59686,00

 

Progetto 2022F5JLSE 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 B53D23021510006