Monitoring the T cell response to spontaneous mammary tumors using a novel transgenic mouse model
Bibliographic record
Abstract
4252 Many human cancers elicit immune recognition but are nevertheless able to persist and disseminate in immunocompetent individuals. Our goal is to characterize the immune response to spontaneously developing mammary tumors and define the mechanisms by which tumors evade rejection by tumor-specific T cells. We have developed a novel transgenic mouse mammary tumor model in which tumor formation is driven by expression of a modified version of HER2/neu. The modified oncogene, designated neuOTI/OTII, was created by addition of CD8+ (OT-I) and CD4+ (OT-II) T cell epitopes from ovalbumin to the C-terminus of HER2/neu. These epitope tags allow neuOTI/OTII to be recognized by T cell receptor (TCR) transgenic CD8+ and CD4+ T cells specific for these epitopes. Such T cells can be labeled and infused into mice expressing neuOTI/OTII, thereby allowing precise monitoring of CD4+ and CD8+ T cell responses to both established and developing mammary tumors. Transgenic mice expressing neuOTI/OTII together with a dominant-negative p53 transgene (DNp53) develop spontaneous mammary carcinomas at 7-10 months of age with an average latency of 8 months. NeuOTI/OTII is strongly expressed in tumors but not in any other tissues examined. Tumors and derived cell lines are positive for MHC Class I and negative for MHC Class II, Fas, FasL and the costimulatory molecules, B7-1 and B7-2. As expected, CD8+ (OT-I) and CD4+ (OT-II) T cells become activated in vitro when exposed to cells expressing neuOTI/OTII. To study the T cell response to spontaneously arising tumors, naive OT-I or OT-II TCR-transgenic T cells were labeled with the fluorescent dye CFSE and adoptively transferred into tumor-bearing neuOTI/OTII x DNp53 mice. At serial time points, T cell proliferation was evaluated by monitoring reduction in CFSE intensity. T cells were also analyzed for expression of cell surface activation markers. In 5/5 mice that received OT-II cells, little or no proliferation was observed in response to neuOTI/OTII x DNp53 tumors, even as late as 13 days post transfer. In 1/1 mouse that received OT-I and OT-II T cells together, OT-I cells began proliferating within 3 days while OT-II cells remained unresponsive. Unexpectedly, tumor progression stabilized within 4 days of T cell infusion and complete tumor regression had occurred by day 10. These preliminary results suggest that established tumors are capable of triggering a strong, potentially curative, CD8+ response, but appear to selectively evade CD4+ cells. We are currently investigating why OT-II T cells fail to respond to spontaneous neuOTI/OTII x DNp53 tumors as well as the requirements for successful tumor eradication by OT-I T cells.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".