Characterizing the role of PRMT5 in macrophages and its impact on the tumour microenvironment
Bibliographic record
Abstract
Protein methyltransferase 5 (PRMT5) is an arginine methylation enzyme and a key regulator of the immune response.The role of PRMT5 is understood to be a suppressor of the innate immune cGAS-STING signalling pathway and is crucial for the proper development of cytotoxic CD8 + T lymphocytes.Depletion of PRMT5 in adaptive immune cells results in cancer progression; however, little is known on the impact of PRMT5 on innate immune cells such as macrophages.Herein, we have identified a new role for PRMT5 in macrophage polarization as well as the regulation of tumor immunity in the tumor microenvironment (TME).We illustrated using a PRMT5 conditional knockout (cKO) macrophage animal model that treatment with IFNg caused an increase in RNA expression of pro-inflammatory macrophage markers compared to control mice, but flow cytometry analysis showed no relative changes in the percentage of macrophage population expressing the pro-inflammatory markers.Macrophages are known to regulate the differentiation and proliferation of certain T lymphocytes.We investigated this using the PRMT5 cKO and we showed that the depletion of PRMT5 in macrophages did not impair the population or subtypes of splenic T lymphocytes.Next, we challenged PRMT5 macrophage cKO mice with subcutaneous injections of syngeneic B16.F0 melanoma.The tumor xenografts of PRMT5 cKO mice had decreased tumor infiltrating lymphocytes (TILs) compared to their control littermates.Lastly, we generated PRMT5 CD4-Cre mice, and we observed decreased CD8 + T-cell with reduced Th1, Th2 and CD4 + Treg cell expansion in the absence of PRMT5.The findings of my thesis show that PRMT5 depletion in macrophage increases the RNA expression of proinflammatory markers.PRMT5 cKO mice developed larger B16.F0 melanoma tumors with a reduction in TILs, promoting tumor progression.Additionally, PRMT5-depletion in T lymphocytes caused a decrease in cytotoxic CD8 + T-cell populations, and decreased CD4 + helper suppress the antiviral immune response, as well as increasing the effects of ICI, I hypothesize that PRMT5 might also be a key regulator of the immune activity of macrophages and lymphocytes.Thus, my first objective was to determine if PRMT5 depletion in bone marrow derived macrophages (BMDM) using the LYZM-CRE driver in PRMT5 Flox/Flox mice influenced the differentiation, polarization, and function of these cells.I also examined whether the differentiation of splenic T-cells occurred normally using the CD4-CRE driver in PRMT5 Flox/Flox mice.The second objective was to analyze the tumour immune microenvironment, as well as tumour size of PRMT5 knockout macrophages mice after subcutaneous injection of B16.F0 melanoma 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) | 0.000 | 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) | 0.001 | 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".