Increased Sirtuin 6 Activity in Tumor Cells Can Prompt CD4-Positive T-Cell Differentiation Into Regulatory T Cells and Impede Immune Surveillance in the Microenvironment
Bibliographic record
Abstract
Background: Sirtuin 6 (Sirt6) is expressed at increased levels in many tumors and may be involved in immunoregulation. The present study investigated how Sirt6 in tumor cells affects immune surveillance. Methods: The human tumor cell lines A2780, HeLa, Huh7, MBA-MD-231, SMMC-7721 and SW480 were incubated with UBCS039, a target-selective activator of Sirt6, to stimulate Sirt6 activity. These cells, following washing to remove residual UBCS039, were cultured with human naive CD4+ T cells in the Transwell to observe the T cell differentiation. Regulatory T cells (Tregs) among CD4+ T cells and the levels of various cytokines and adenosine (ADO), an immunosuppressive metabolite, in the culture medium, were measured via flow cytometry. The treated tumor cells were examined via transcriptomic analysis. The transcriptomic results, as well as programmed cell death protein-1 (PD-1), programmed cell death-ligand 1 (PD-L1) and Sirt6 expression in tumor cells and CD4+ T cells were verified via real-time polymerase chain reaction (PCR). Results: Following culture with UBSC039-pretreated tumor cells, the proportion of Tregs among CD4+ T cells was significantly increased. PD-L1 and Sirt6 expressions in UBS039-pretreated tumor cells and PD-1 expression in cocultured CD4+ T cells were also increased. Moreover, the ADO level increased, and the interleukin (IL)-10, interferon (IFN)-α2, IFN-γ and monocyte chemoattractant protein-1 (MCP-1) levels decreased in the coculture medium. Transcriptomic analysis revealed significant downregulation of the antitumor genes BASP1, CPS1, GNG11, MFAP5, NNMT and SMOC1, upregulation of the tumor-promoting genes FOXA2, GSTP1, RASEF and ZNF844, and activation of adherens junctions, tumor necrosis factor (TNF)-signaling and the circadian rhythm pathway in UBCS039-pretreated SMMC-7721 cells. The above results were verified in all six cell lines. Conclusions: The present study suggested that increased Sirt6 expression and activity in tumor cells can suppress immune surveillance by increasing Treg, ADO, PD-1 and PD-L1 levels, decreasing IFN-γ production, and altering tumor-promoting and antitumor gene expression in the microenvironment.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".