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ReverT

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Reversing T cell dysfunction in cancer by multimodal genetic screening

T cell dysfunction is a key problem in cancer, enabling not only tumorigenesis but also causing resistance to immunotherapy. Induction of immune checkpoints is a hallmark of T cell dysfunction, but clinical blockade by PD-1 and CT... ver más

30/09/2027

NKI AVL

2M€

Presupuesto del proyecto: 2M€

Líder del proyecto

STICHTING HET NEDERLANDS KANKER INSTITUUTANTO... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2022-10-01

ERC-2021-ADG: ERC ADVANCED GRANTS Scope:Objectives

I+D

Cerrada hace 3 años

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No hay información privada compartida para este proyecto. Habla con el coordinador.

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NKI AVL

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Duración del proyecto: 59 meses Fecha Inicio: 2022-10-01
Fecha Fin: 2027-09-30

Líder del proyecto

STICHTING HET NEDERLANDS KANKER INSTITUUTANTO... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 2M€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto T cell dysfunction is a key problem in cancer, enabling not only tumorigenesis but also causing resistance to immunotherapy. Induction of immune checkpoints is a hallmark of T cell dysfunction, but clinical blockade by PD-1 and CTLA-4 antibodies solves this problem for few patients only. Dysfunction is driven also by additional mechanisms, including chronic stimulation and metabolic insufficiency. A better mechanistic understanding will be imperative for improving immunotherapy. My laboratory recently launched “ReverT”, a genome-wide CRISPR-Cas9 screening program to identify genes, ablation of which reverses dysfunction in primary T cells. To de-risk this application, we have already successfully completed three such screens in vitro, for chronic antigen stimulation, metabolic stress and PD-1 induction, validating and characterizing several dysfunction genes not previously reported. Furthermore, an independent follow-up re-screen with a Dysfunction Reversion Candidate (DRC) mini-library containing the top 100 hits of each of these screens validated >100 genes that reversed T cell dysfunction in vitro. Here, we will carry out the most challenging and important step: to systematically validate and mechanistically characterize this collection of T cell dysfunction genes in vivo. This will be done in a pooled and multimodal fashion, analyzing multiple dysfunction phenotypes in parallel, specifically immune checkpoints, exhaustion, metabolism, recruitment and proliferation. Our proof-of-concept results indicate that the DRC library contains “nodal” factors, operating in several seemingly different dysfunction settings, which may thus in fact be linked. We will use a collection of adoptive cell transfer mouse and human tumor models for validation and mechanistic characterization, as well as primary human T cells in patient-derived tumor fragments. Lastly, we will translate our findings to a preclinical setting, aiming to achieve more durable clinical responses.

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