Tumor suppressor pathways counteracting oncogenic immune receptor signaling in T-Cell Lymphoma

Informazioni relative al progetto

T-NHL SUPRESSORS

ID dell’accordo di sovvenzione: 834154

DOI

10.3030/834154

Progetto chiuso

Data della firma CE 4 Giugno 2019

Data di avvio 1 Dicembre 2019

Data di completamento 30 Novembre 2025

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 2 492 937,50

Contributo UE

€ 2 492 937,50

Coordinato da

KLINIKUM DER TECHNISCHEN UNIVERSITÄT MÜNCHEN (TUM KLINIKUM)
Germany

Periodic Reporting for period 4 - T-NHL SUPRESSORS (Tumor suppressor pathways counteracting oncogenic immune receptor signaling in T-Cell Lymphoma)

Periodo di rendicontazione: 2024-06-01 al 2025-11-30

Sintesi del contesto e degli obiettivi generali del progetto

Aggressive T-cell non-Hodgkin lymphomas (T-NHLs) remain poorly treatable malignancies with limited targeted therapies. Genomic studies identified recurrent inactivation of the immune checkpoint receptor PD-1 (PDCD1) as a hallmark of advanced disease associated with poor prognosis and paradoxical hyperprogression upon checkpoint blockade. This project addressed the unresolved question of how PD-1 functions as a tumor suppressor within malignant T cells. The overarching objective was to define the intrinsic molecular mechanisms by which PD-1 restrains T-cell transformation and progression. We aimed to uncover actionable metabolic and epigenetic dependencies downstream of PD-1 loss to enable genotype-informed therapeutic strategies for T-cell lymphoma.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

The project combined genetically defined mouse models, metabolic flux analyses, epigenomic profiling, and primary human T-NHL samples. We demonstrated that PD-1 enforces a tumor-suppressive metabolic program by restricting PI3K–AKT–mTOR–HIF1α–driven glycolysis. Loss of PD-1 promoted ATP citrate lyase–dependent acetyl-CoA production, increased histone acetylation, chromatin accessibility, and aberrant activation of AP-1 transcription factors. These mechanisms were conserved in human PDCD1-deficient and hyperprogressive T-NHL. Importantly, PD-1 loss created selective therapeutic vulnerabilities to mTOR, glycolysis, and ACLY inhibition. Results were disseminated through high-impact publications and public multi-omics datasets.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

This project establishes PD-1 as a cell-intrinsic metabolic and epigenetic gatekeeper in T-cell lymphoma, extending its role far beyond immune checkpoint regulation. We define a previously unrecognized PD-1–controlled metabolic–epigenetic axis linking glycolysis, acetyl-CoA availability, histone acetylation, and AP-1–driven oncogenic transcription. This conceptual advance provides a mechanistic explanation for PD-1–associated hyperprogression and identifies genotype-specific vulnerabilities in PDCD1-mutant T-NHL. By project completion, we delivered robust preclinical evidence supporting biomarker-guided targeting of mTOR, glycolysis, or ACLY, laying the groundwork for stratified clinical trials and precision therapy approaches in aggressive T-cell lymphomas.

PD-1 loss drives ACLY-dependent histone acetylation to activate oncogenic AP-1.