Blockade of colon cancer metastasis via single and double silencing of <i>PCSK7</i> / <i>PCSK9</i> : enhanced T cells cytotoxicity in mouse and human
Bibliographic record
Abstract
Background Immunotherapy approaches based on T cells provided breakthroughs in cancer treatment but could cause many immune-related adverse events, and their efficacy is limited for many cancers with an acquired dysfunction/exhaustion of T cells. The present study presents a novel role in immunity for proprotein convertase subtilisin-kexin 7 (PCSK7), the seventh proprotein convertase of the 9-membered secretory proprotein convertase subtilisin-kexin (PCSK)-family. Methods We analyzed cell surface levels of various immune checkpoint proteins in human and mouse cell models in the presence or absence of PCSK7 expression. Injection of mouse colon carcinoma MC38 cells in the spleen of mice lacking either Pcsk7 , Pcsk9 or both (double knockout) allowed the analysis of the extent of hepatic tumor metastasis. We also estimated the cell surface expression of checkpoint proteins in CD4 + and CD8 + T cells from healthy human subjects in which PCSK7 expression was silenced by CRISPR Cas9 gRNA knockdown. Results Bioinformatic and cellular studies showed enrichment of PCSK7 mRNA levels in CD8 + T cells, which correlates with those of immune checkpoint proteins (ICPs; eg, LAG3 , CTLA4 , PD1 and TIGIT ) responsible for T-cell dysfunction. Indeed, cells lacking PCSK7 and CD8 + T cells derived from Pcsk7 −/− mice exhibited ≥40% lower cell-surface levels of ICPs. Similarly, CRISPR-Cas9 editing of PCSK7 ( PCSK7 i) in primary human T cells resulted in lower expression of ICPs and a reduced proportion of cells expressing multiple ICPs, without altering the expression of activation markers. Moreover, proprotein convertase subtilisin-kexin 9 (PCSK9), the ninth PCSK family member, enhances the degradation of the low-density lipoprotein-receptor and major histocompatibility complex-I proteins. Indeed, Pcsk9 −/− mice were previously reported to exhibit reduced liver tumor metastasis. In the present studies, we report synergistic and complementary functions of PCSK7 and PCSK9, as the loss of each one of the convertases reduced by twofold the number of liver metastases, but the strongest reduction (>90%) was observed in double KO ( Pcsk7 −/− , Pcsk9 −/− ) mice. In Pcsk7 −/− mouse tumors the antitumorigenic activity of CD8 + T cells was enhanced and the levels of ICPs were reduced. Conclusions Cumulatively, our data provide a PCSK7 i strategy to reduce the levels of cell-surface ICPs, thereby rationalizing the use of PCSK7 i in T-cell immunotherapies alone or in combination with a PCSK9 inhibitor/silencer.
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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".