Effect of Platelets and their Pharmacological Regulation on Cancer Cell Immune Checkpoint PD‐L1 Expression
Bibliographic record
Abstract
Background Cancer cells have the ability to activate platelets, and platelets play an important role facilitating hematogenous metastasis. One mechanism by which platelets promote metastasis is their ability to shield cancer cells from natural killer cell‐mediated death. Although much is known of how platelets affect the innate immune response, our understanding of platelet function in modulating the adaptive immune system in cancer is limited. A major negative regulator of the adaptive immune response in cancer is the immune checkpoint transmembrane protein Programmed Death Ligand 1 (PD‐L1). PD‐L1 interacts with its receptor PD on T‐cells resulting in T‐cell anergy and/or apoptosis. This cancer cell survival mechanism is exploited in various types of cancer, including lung and kidney. Interestingly, platelets upon activation secrete a number of factors that have the potential to increase cancer cell PD‐L1 expression. Therefore, we hypothesized that cancer cell‐activated platelets increase cancer cell PD‐L1 expression and that common anti‐platelet drugs inhibit this platelet‐induced up‐regulation of PD‐L1. Methods Platelets were isolated from the blood of healthy human volunteers. Human A549 lung and 786‐O renal cancer cells were incubated with and without platelets for 24 hours and cancer cell PD‐L1 surface expression was measured by flow cytometry and mRNA by qPCR. In other experiments, platelet‐cancer cell incubations were performed in the presence of anti‐platelet drugs acetylsalicylic acid (ASA – 100 mM), Prasugrel active metabolite (PAM – 10 mM) or Integrelin (10 mM). Results Platelets caused a significant increase in PD‐L1 surface expression by A549 (6.7±3.1% of A549 vs. 16.3±3.9% of A549 + platelets, P < 0.05 ) and 786‐0 cells (11.2±3.1% of 786‐O vs. 21.8±4,8% of 786‐O + platelets, P < 0.05 ). This increase in surface expression occurred as a result of a 3‐fold increase in PD‐L1 mRNA in A549 incubated with platelets. Platelets did not express PD‐L1 mRNA. Importantly, anti‐platelet drugs Prasugrel active metabolite (PAM) and Integrelin, but not acetylsalicylic acid, prevented the platelet‐dependent increase in PD‐L1 expression by A549. Conclusions Platelets up‐regulate the transcriptional expression of PD‐L1 by cancer cells, and Prasugrel and Integrelin can inhibit this up‐regulation. Further experiments are needed to determine whether platelet‐induced expression of PD‐L1 on cancer cells protects them from T‐cell induced death, and whether investigation of anti‐platelet drugs as adjuvant therapy in addition to immune checkpoint inhibitors is warranted. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0.001 |
| 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".