Karina Lobo Hajdu

The accumulation of depolarized mitochondria commits T cells to exhaustion ^1–3 , yet the precise mechanism remains unclear. Here we find that exhausted CD8 ⁺ T cells increase proteasome activity owing to the accumulation of depolarized mitochondria, which drives the selective degradation of mitochondrial proteins and the release of regulatory haem through haemoprotein breakdown. In turn, increased regulatory haem disrupts BACH2-mediated transcriptional regulation, thereby exacerbating T cell exhaustion and compromising stemness-like properties. Inhibition of nuclear import of regulatory haem prevents BACH2 degradation and enhances the anti-tumour efficacy of antigen-specific T cells. We find that the therapeutic efficacy of human CD19 ⁺ chimeric antigen receptor (CAR)-T cells in patients with B cell acute lymphoblastic leukaemia negatively correlates with the proteasome gene signature in their CAR-T cells. Manufacturing CAR-T cells in the presence of bortezomib, an FDA-approved proteasome inhibitor, prevents T cell exhaustion and improves therapeutic efficacy. Our findings identify a proteasome-guided haem signalling axis, governed by mitochondrial integrity, as a regulator of CD8 ⁺ T cell exhaustion and propose innovative therapeutic strategies that exploit this pathway to optimize adoptive cellular immunotherapy.

Chimeric antigen receptor (CAR) T-cell therapy is increasingly being adopted as a clinical modality for patients with relapsed/refractory hematologic malignancies. Despite the clinical efficacy of CAR T-cell therapy, a considerable fraction of patients still relapse during the first months following CAR T-cell infusion. The limited CAR T-cell efficiency is thought to relate to epigenetic mechanisms involved in T-cell suppression and dysfunction. In this study, screening of multiple epigenetic inhibitors revealed that targeting polycomb repressive complex 2 (PRC2) consistently induced the development of granzyme B+ effector memory CD8 T cells. Notably, PRC2 inhibition also promoted the long-term persistence of granzyme B+ effector memory 19BBζ CAR T cells and enhanced sustainably their antitumor activity both in vitro and in vivo. Consistent with their long-lasting antitumor activity, PRC2-inhibited 19BBζ CAR T cells did not exhibit signs of exhaustion over time. Furthermore, TCR restimulation along with PRC2 inhibition promoted the differentiation of patient-derived anti-CD19 effector memory CAR T cells with enhanced cytotoxic features and elicited potent antitumor responses. In line with this, the gene signature derived from in-house PRC2-inhibited 19BBζ CAR T cells was enriched in tisagenlecleucel BBζ CAR T-cell therapy responders with large B-cell lymphoma. Collectively, our results demonstrated that targeting PRC2 may be a promising approach to enhance a functional effector program in CAR T cells against hematologic malignancies. Significance: Selective inhibition of PRC2 endows 19BBζ CAR T cells with cytotoxic and effector memory features that are associated with improved antitumor activity and better response to CAR T-cell therapy.

The ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines are reportingguidelines designed to improve transparency and facilitate critical assessment ofexperiments involving animal research. Although it represents essential reportinginformation for animal experiments, compliance with ARRIVE items is not commonlydemanded by journals and is often lacking in animal studies. In this small pilot project, weevaluated compliance with ARRIVE 2.0 essential 10 items in 64 papers from 2018 and 2020,either citing or not the ARRIVE manuscripts. Papers that cited the ARRIVE guidelines hadslightly higher reporting scores, but we did not detect an effect of the time period nor aninteraction effect between ARRIVE versions 1.0 and 2.0. This work was conducted during theNo-Budget Science Hack Week 2021 event, an extended hackathon to discuss and developprojects in metascience. In future work, this pilot can be expanded to better estimate theeffects of the ARRIVE guidelines on reporting practices.

Throughout the global coronavirus pandemic, we have seen an unprecedented volume of COVID-19 researchpublications. This vast body of evidence continues to grow, making it difficult for research users to keep up with the pace of evolving research findings. To enable the synthesis of this evidence for timely use by researchers, policymakers, and other stakeholders, we developed an automated workflow to collect, categorise, and visualise the evidence from primary COVID-19 research studies. We trained a crowd of volunteer reviewers to annotate studies by relevance to COVID-19, study objectives, and methodological approaches. Using these human decisions, we are training machine learning classifiers and applying text-mining tools to continually categorise the findings and evaluate the quality of COVID-19 evidence.

We discuss in this News and Commentary article the implications of senolytic chimeric antigen receptor T cells.

Background: Preprint usage is growing rapidly in the life sciences; however, questions remain on the relative quality of preprints when compared to published articles. An objective dimension of quality that is readily measurable is completeness of reporting, as transparency can improve the reader’s ability to independently interpret data and reproduce findings. Methods: In this observational study, we initially compared independent samples of articles published in bioRxiv and in PubMed-indexed journals in 2016 using a quality of reporting questionnaire. After that, we performed paired comparisons between preprints from bioRxiv to their own peer-reviewed versions in journals. Results: Peer-reviewed articles had, on average, higher quality of reporting than preprints, although the difference was small, with absolute differences of 5.0% [95% CI 1.4, 8.6] and 4.7% [95% CI 2.4, 7.0] of reported items in the independent samples and paired sample comparison, respectively. There were larger differences favoring peer-reviewed articles in subjective ratings of how clearly titles and abstracts presented the main findings and how easy it was to locate relevant reporting information. Changes in reporting from preprints to peer-reviewed versions did not correlate with the impact factor of the publication venue or with the time lag from bioRxiv to journal publication. Conclusions: Our results suggest that, on average, publication in a peer-reviewed journal is associated with improvement in quality of reporting. They also show that quality of reporting in preprints in the life sciences is within a similar range as that of peer-reviewed articles, albeit slightly lower on average, supporting the idea that preprints should be considered valid scientific contributions.