Abstract B05: An immune modulatory role for the Fes protein tyrosine kinase
Bibliographic record
Abstract
Abstract The Fes protein tyrosine kinase is abundantly expressed in phagocytic immune cells, including tumor associated macrophages. In addition to the C-terminal kinase and central SH2 domains, Fes contains an N-terminal F-BAR domain that confers unique membrane binding and bending properties which implicate it in the regulation of dynamic membrane-cytoskeletal remodeling processes associated with phagocytosis, receptor endocytosis, vesicular trafficking and cross-talk between receptor systems. In addition to roles in signaling downstream from a variety of cytokine receptors, including those for IL-3, -4, -5, and GM-CSF, Fes has also been implicated in regulating signaling downstream from the TLR-4 receptor for LPS. Fes knockout mice display enhanced sensitivity to LPS, and this was shown to be associated with increased NF-κB signaling and TNFα production from Fes-/- macrophages. Recent studies have also implicated Fes in cross-talk between MHC-I and the NF-κB and IRF-3 pathways in macrophages. Activation of these pro-inflammatory NF-κB and IRF-3 pathways so called Signal 3 - in antigen presenting cells (APCs) is associated with more robust activation of T cells. Interestingly, tumor onset in the MMTV-Neu transgenic mouse model of breast cancer is significantly delayed in Fes-/-, and this was associated with increased frequency of T and B lymphocytes in the premalignant mammary glands. These observations suggest that Fes contributes to the regulation of signaling downstream from the MHC-I and TLR receptors such that Fes disruption in TLR-engaged APCs would lead to enhanced activation of CD8+ T cells through increased Signal 3 from the T-cell receptor-engaged APCs. Using a lymphocytic choriomeningitis virus (LCMV) model of immune activation we show that LPS stimulated Fes-/- macrophages promote more robust activation of CD8+ T cells than Fes+/+ macrophages. Furthermore, LPS stimulated Fes-/- macrophages show increased phosphorylation of TBK-1 and IRF-3. We also observed that Fes co-localizes with MHC-I in dynamic vesicular structures within macrophages. These observations are consistent with a model where Fes regulates Signal 3 in APCs through roles in cross-talk between MHC-I and the NF-kB and IRF-3 signaling pathways. This suggests that Fes plays an immune checkpoint role at the level of Signal 3, and that Fes inhibition could promote tumor immunity through increased Signal 3 driven T cell activation. Citation Format: Faizah Mesfer Alotaibi, Connie Zhang, Sam Basta, Peter A. Greer. An immune modulatory role for the Fes protein tyrosine kinase. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B05.
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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) | 0.004 | 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".