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

Información del proyecto

T-NHL SUPRESSORS

Identificador del acuerdo de subvención: 834154

DOI

10.3030/834154

Proyecto cerrado

Fecha de la firma de la CE 4 Junio 2019

Fecha de inicio 1 Diciembre 2019

Fecha de finalización 30 Noviembre 2025

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 2 492 937,50

Aportación de la UE

€ 2 492 937,50

Coordinado por

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)

Período documentado: 2024-06-01 hasta 2025-11-30

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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.