193. RORY+ NEUTROPHILS: A NOVEL THERAPEUTIC TARGET IN GASTRO-ESOPHAGEAL ADENOCARCINOMA
Bibliographic record
Abstract
Abstract Background High neutrophil-to-lymphocyte ratio (NLR) is associated with worse oncological outcomes. No current therapies target this emergency myelopoiesis-driven (EM) phenotype. EM, driven by retinoic-acid orphan receptor gamma (RORy), is the phenomenon where cancer cells secrete various factors, skewing normal hematopoiesis towards increased production of pro-tumour RORy+ neutrophils. These neutrophils correlate with advanced stage disease. Additionally, RORy ablation reduces tumour burden in vivo. Our study explores the undescribed roles and therapeutic potential of RORy+ neutrophils in GEA. Methods: Peripheral blood collected from treatment-naïve GEA patients were lysed and stained for flow cytometry for the following markers: CD66b, CD11b, RORy, interleukin-17 (IL-17) and programmed death-ligand 1 (PD-L1).5x106 YTN16-GFP cells, a murine gastric cancer cell line, were injected in the flank of C57Bl/6 mice. 7 days post-tumour inoculation, 25 mg/kg of a novel experimental RORy inhibitor (Compound #10) was injected subcutaneously on a daily basis till endpoint. Tumour size and circulating NLR were monitored on a weekly basis throughout the experiment. Blood and tumour were also collected at endpoint and stained for flow cytometry. Results Our data demonstrate that: Treatment-naïve GEA patients with a high NLR (NLR > 4) have increased prevalence of circulating RORy+ neutrophils compared to low NLR (NLR < 4) GEA patients and healthy volunteers.Circulating RORy+ neutrophils have a higher expression of PD-L1 and IL-17 compared to RORy (−) neutrophils, hinting towards a pro-inflammatory and immunosuppressive phenotype.Anti-RORy treatment in a murine gastric cancer model results in reduced tumour burden and reduced percentage of intratumoural RORy+ neutrophils. Treated mice also exhibited a less immunosuppressive intratumoural microenvironment. Conclusion We are the first to associate a high circulating NLR with higher prevalence of circulating RORy+ neutrophils in GEA, thus demonstrating evidence of emergency myelopoiesis in those patients. Additionally, we show that RORy+ neutrophils are a major player in cancer progression. More importantly, these results define a novel therapeutic target that can be utilized to improve patient outcomes, namely GEA patients with a high NLR, a patient subgroup known to have worse outcomes.
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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) | 0.001 | 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".