Objective
Cancer-directed T cell therapies such as CAR T cells depend on TCR–CD3 activation. While curative in acute leukemias, responses in most other cancers remain modest. Chronic lymphocytic leukemia (CLL), the most common leukemia, is a prototypical setting of tumor-induced T cell dysfunction: it remains incurable and autologous T cell therapies provide little benefit. Current dogma explains this failure by two factors: inhibitory signals in the tumor microenvironment reduce CD3 activation, and limited nutrients restrict glycolysis. Together these impair metabolism and T-cell function.
My group introduces an alternative concept. Cancer-mediated T cell dysfunction is metabolically mediated, but not due to insufficient nutrients or glycolysis. Instead, it stems from mitochondrial failure: OXPHOS, essential for proliferation, effector programming and persistence, cannot be engaged. Not too little activation, but distorted and persistent CD3 signaling is the cause. Activation-induced signals fail to attenuate, driving abnormal lipid remodeling and defective mitophagy, leading to accumulation of dysfunctional mitochondria.
Crucially, this failure is reversible. We discovered that selective engagement of an alternative T-cell signaling axis provides a CD3-independent route to restore OXPHOS, proliferation and effector function. This mechanism, validated in colorectal carcinoma, overturns prevailing concepts and identifies mitochondrial regulation and non-canonical signaling as therapeutic opportunities.
The overall aim is to restore competence of tumor-exposed T cells by:
1. Decoding canonical versus alternative T-cell signaling pathways;
2. Elucidating mechanisms of activation-induced mitophagy suppression;
3. Identifying transcriptional regulators of mitochondrial fitness;
4. Developing next-generation signaling-based strategies for T-cell therapies.
This high-risk, high-gain program reframes T cell dysfunction in cancer as signaling-driven mitochondrial failure and opens new routes to extend the curative potential of autologous T cells across cancers.
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2025-ADG
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1081 HV Amsterdam
Netherlands
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