Abstract B005: Molecular, metabolic and functional CD4 T cell paralysis in lymph node impedes tumor control
Bibliographic record
Abstract
Abstract Introduction: CD4 T cells are important in anti-tumor immunity, yet the regulation of CD4 tumor-specific T (TTS) cells during cancer development is still unclear. So far, studies have primarily focused on studying bulk CD4 tumor-infiltrating lymphocytes (TILs) with unknown antigen specificities, or transferring in vitro activated CD4 T cells as adoptive cell therapy (ACT), which fail to directly address how naïve CD4 TTS cells are activated and then differentiate in vivo in response to tumor progression. Therefore, studies addressing these questions will be critical to understand the state of anti-tumor CD4 T cells available for restorative therapies. Methods: To address these key questions, we developed two murine tumor cell lines, PyMG (an orthotopic breast tumor) and MC38GP (an adenocarcinoma tumor) expressing the LCMV glycoprotein 1-100 sequence (LCMV-GP1-100). The sequence contains an MHCII-epitope GP61-80 and an MHCI-epitope GP33-43, that can be recognized by TCR transgenic CD4 T cells (SMARTAs) and CD8 T cells (P14s), enabling direct in vivo identification of CD4 TTS cells. Results: We demonstrate that following tumor initiation, CD4 TTS cells are initially primed in the tumor draining lymph node (dLN), but rapidly frozen into a “paralyzed” state. The paralyzed state freezes CD4 TTS cell clonal expansion, impairs differentiation, limits IFNγ production, and redirects metabolic circuits, which together impede tumor control. Transcriptional programming of CD4 TTS cell paralysis is unique to the tumor setting and distinct from well-defined effector and exhaustion programming. In comparison, CD8 TTS cells do not manifest the proliferation defect. Paralysis is actively maintained throughout cancer progression by a functional interplay of regulatory T cells (Tregs) and CTLA4. Depleting Tregs induces robust proliferation of CD4 TTS cells, yet concurrently pushes the proliferated cells to become highly suppressive tumor-specific induced Tregs (iTregs). The differentiation of iTregs is dependent on the CTLA4 expression on CD4 TTS cells. Alleviating suppressive signals from both Tregs and CTLA4 is required to restore CD4 TTS cells proliferation, reduce iTreg differentiation and promote T helper cell differentiation. Overcoming CD4 TTS cell paralysis established long-term tumor control, demonstrating a novel immune evasion mechanism that specifically cripples CD4 TTS cells to favor tumor progression. Conclusion: Our study demonstrates that during early stages of cancer, the CD4 TTS cell development is quickly paralyzed at multiple levels of functional development. Overcoming their paralysis established long-term tumor control, demonstrating a novel immune evasion mechanism that specifically cripples CD4 TTS cells to favor tumor progression. Citation Format: Mengdi Guo, Diala Abd-Rabbo, Bruna Bertol, Madeleine Carew, David G Brooks. Molecular, metabolic and functional CD4 T cell paralysis in lymph node impedes tumor control [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B005.
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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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".