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.

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.

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.

This work could redefine strategies to overcome ICB resistance, leveraging apoptosis modulation to restore immune surveillance.