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- Exploring the role of Bcl-2 family in the immune surveillance of melanoma: from mechanisms to therapeutic perspectives
- Exploring how endothelin-1/PIEZO axis intersects mechanical forces to fuel PARP inhibitor resistance in ovarian cancer
Exploring the role of Bcl-2 family in the immune surveillance of melanoma: from mechanisms to therapeutic perspectives
Project description
PI: Marta Di Martile
Other IRE Principal Collaborators: Di Caprio Marica, Gentile Giulia, Scalera Stefano, Valentini Elisabetta, D’Aguanno Simona, Ercolani Cristiana, Nisticò Paola, Pelle Fabio, Russillo Michelangelo, Terrenato Irene
Project Code: 30677
Project Duration:60 months
This project investigates the synergistic potential of Bcl-2 inhibition with immune checkpoint blockade (ICB) to overcome therapy resistance in metastatic melanoma. The study integrates multi-omics approaches (single-cell transcriptomics, TCRαβ repertoire profiling) and patient-derived organotypic cultures (PDOCs) to dissect mechanisms of immune evasion and therapeutic response. Key components include:
WP1: Characterization of Bcl-2’s role in CD8+ T-cell dysfunction within the tumor microenvironment (TME) using murine models and human samples.
WP2: Preclinical testing of Bcl-2 inhibitors (venetoclax) combined with ICB (anti-PD-1/anti-CTLA-4), evaluating toxicity, immune reprogramming (single-cell RNA-seq of CD45+ cells), and TCR clonality.
WP3: Validation in PDOCs from melanoma metastases to assess personalized drug responses.
Purpose
The study aims to:
- Decipher immune resistance mechanisms driven by Bcl-2 in CD8+ T cells and the TME.
- Develop a novel combinatorial therapy (Bcl-2i + ICB) to reinvigorate antitumor immunity.
- Bridge preclinical and clinical research using PDOCs for patient-stratified predictions.
Expected Results
Mechanistic insights: Bcl-2’s regulation of CD8+ T-cell exhaustion and immunosuppressive TME networks.
Therapeutic validation: Enhanced ICB efficacy and survival in murine models with Bcl-2i combinations.
Translational outcomes:
- Identification of biomarkers (e.g., TCR clonality, EV cargo) predictive of response.
- PDOC-based evidence supporting personalized combinatorial regimens.
- Clinical relevance: Rationale for trials testing Bcl-2i/ICB in melanoma, with preliminary safety data.
Impact
This work could redefine strategies to overcome ICB resistance, leveraging apoptosis modulation to restore immune surveillance.
Financial Support
AIRC Associazione Italiana per la Ricerca sul Cancro My First AIRC Grant
The total grant of the project is: ca. €500.000,00
The European Regional Development Fund (ERDF) aims to consolidate economic and social cohesion in the European Union by correcting any disparities that may exist between regions.
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