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

Project Information

T-NHL SUPRESSORS

Grant agreement ID: 834154

DOI

10.3030/834154

Project closed

EC signature date 4 June 2019

Start date 1 December 2019

End date 30 November 2025

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 492 937,50

EU contribution

€ 2 492 937,50

Coordinated by

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)

Reporting period: 2024-06-01 to 2025-11-30

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.