OGG1 activation improves T cell resilience to oxidative stress after allo-SCT and T cell engager exposure
Bibliographic record
Abstract
Relapse remains the major cause of treatment failure after allogeneic stem cell transplantation (allo-SCT), often related to impaired immune surveillance by donor-derived T cells. Oxidative stress is a hallmark of allo-SCT leading to accumulation of oxidized DNA lesions, most notably 8-hydroxy-2’-deoxyguanosine (8-ohdg) in reconstituting T cells [ 1 ]. High 8-ohdg level correlated with impaired functionality and increased relapse risk [ 1 ]. The clinical success of histamine dihydrochloride, an antioxidant agent, in combination with interleukin-2 for relapse prevention in AML highlights the therapeutic relevance of redox modulation to restore T and NK cell functionality [ 2 ]. Sustained stimulation of the T cell receptor (TCR) in alloreactive T cells results in mitochondrial hyperreactivity and abundant superoxide generation [ 3 ]. Oxidized bases lead to replication stress and double-strand breaks, which not only impair gene expression but also induce premature senescence, a state that limits efficacy of T cell-based therapies. T cell fitness, which encompasses metabolic resilience and adaptability, has emerged as a key determinant of successful immune reconstitution and therapeutic efficacy [ 4 ]. In fact, DNA integrity, particularly resistance to oxidative DNA damage, is an underappreciated facet of T cell fitness, as DNA damage accelerates T cell aging [ 5 ]. In this context, “DNA fitness” emerges as a potential prerequisite for sustained T cell function. The DNA-glycosylase OGG1 is the key enzyme initiating base excision repair of 8-ohdg, thereby maintaining genomic stability [ 6 ]. Recent work has identified TH10785, a small-molecule OGG1 activator, which enhances its repair activity [ 7 ]. Therapeutic benefit of OGG1 activation has already been demonstrated in preclinical models, where it improved tissue function [ 8 ]. Here, we explore the potential of OGG1 activation as a strategy to restore and preserve T cell function under oxidative stress. By improving DNA repair capacity, we aim to improve T cell-based therapies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".