Christoph Bock Lab @ CeMM & MedUni Vienna

Systematic discovery of CRISPR-boosted CAR T cell immunotherapies - Nature CELLFIE, a CRISPR platform for optimizing cell-based immunotherapies, identifies gene knockouts that enhance CAR T cell efficacy using in vitro and in vivo screens.

📑 Check out our paper titled “Systematic discovery of CRISPR-boosted CAR T cell immunotherapies” at @Nature (open access): www.nature.com/articles/s41.... Feedback & suggestions are very welcome. (13/13)

🤝 This was a large project & great teamwork by: P. Datlinger*, E.V. Pankevich*, C.D. Arnold*, N. Pranckevicius, J. Lin, D. Romanovskaia, M. Schäfer, F. Piras, A.-C. Orts, A. Nemc, P. Biesaga, M. Chan, T. Neuwirth, A. Artemov, W. Li, S. Ladstätter, T. Krausgruber, C. Bock (12/13)

⚕️ Our CELLFIE platform supports clinical translation of CRISPR-boosted CAR T cells. For example, to avoid the DNA double-strand breaks introduced by CRISPR knockout, we performed a tiling base-editing screen across RHOG and identified promising gRNA for clinical testing. (11/13)

🔥 What’s next? Our discovery of strong combined effects for RHOG & FAS knockout underlines the potential of synergistic gene edits for boosting CAR T cell function. We thus integrated combinatorial screening into CELLFIE, using the Blainey lab’s CROPseq-multi method. (10/13)

🔬 From a technical perspective, we are excited how our new in vivo CROP-seq method improves gRNA detection (reading from an mRNA transcript as in nature.com/articles/nme...) and reduces experimental noise (by using UMIs), which enables larger screens with fewer mice. (9/13)

💪 We also observed prolonged survival for FAS knockout CAR T cells, likely because these cells are less effective at killing each other (“fratricide”). Combining RHOG & FAS knockout, we obtained more & better CAR T cells, which further improved survival in leukemic mice. (8/13)

🔍 RHOG is a small GTPase involved in cell signaling. How does it influence CAR T cells ? We found that RHOG knockout increases the proliferative capacity of CAR T cells and helps them retain a highly functional state with reduced exhaustion and enhanced memory phenotype. (7/13)

🐁 We performed extensive in vivo validations and found that RHOG knockout CAR T cells achieve strong reductions in cancer cell numbers and prolonged survival in an aggressive mouse model of human leukemia, with consistent results across different CARs and T cell donors. (6/13)

🐭 But not everything that makes CAR T cells proliferate or kill better in vitro translates into more effective therapies. For scalable validation in mice, we conducted pooled in vivo CRISPR screening and observed strong positive effects of RHOG, PRDM1, and FAS knockouts. (5/13)

💡 Conceptually, our CRISPR screens create a form of “artificial evolution” by which we optimize CAR T cells for their tasks as cancer therapeutics. This is important because CAR T cells are products of cell engineering and lack task-specific evolutionary optimization. (4/13)

🩸 Using CELLFIE, we conducted 58 genome-wide CRISPR screens, with readouts for CAR T cell proliferation, target cell recognition, activation, apoptosis & fratricide, and exhaustion. The screens identified known genes (PD-1, CTLA4, TIM3, TIGIT etc.) and promising new hits. (3/13)

⚙️ We developed CELLFIE (“cell engineering for immunotherapy enhancement”), a CRISPR platform to make & test gene-edited CAR T cells at scale. CELLFIE supports in vitro & in vivo screens with various clinically relevant readouts, plus combinatorial & base-editing screens. (2/13)

🧬 CAR T cells demonstrate the power of engineered cells as therapeutics. But they fail for most patients. Can CRISPR help here? Our new paper in Nature (www.nature.com/articles/s41...) presents a screening platform to optimize immunotherapies & discover boosters of CAR T cell function. (1/13)

Dr. Christoph Bock is a Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor of Medical Informatics at the Medical University of Vienna. His research combines experimental biology (single-cell sequencing, epigenetics, CRISPR screening, synthetic biology) with computational methods (bioinformatics, machine learning, artificial intelligence) – for cancer, immunology, and precision medicine (https://www.bocklab.org & https://bsky.app/profile/bocklab.bsky.social).

We’re thrilled to announce that the "High-Content CRISPR Screening" conference will take place on March 18–19, 2026, in Vienna, Austria.

The registration is now open via the conference website:
lnkd.in/d8KACZy5

Meet the Speaker: Christoph Bock

@bocklab.bsky.social

Integrated time-series analysis and high-content CRISPR screening delineate the dynamics of macrophage immune regulation Traxler, Reichl, et al. combine multi-omics time series with high-content CRISPR screens to identify regulators of macrophage immune responses and map their functional similarities. This study reveals...

🚀 Check out the paper, dataset, and computational methods (open access | open data | open source):
📑 Paper: www.cell.com/cell-systems...
🧬 Dataset: macrophage-regulation.bocklab.org
💻 Code: github.com/epigen/macro...
Feedback & suggestions are very welcome. (9/9)

🤝 Great teamwork by: Peter Traxler*, Stephan Reichl*, Lukas Folkman, Lisa Shaw, Victoria Fife, Amelie Nemc, Djurdja Pasajlic, Anna Kusienicka, Daniele Barreca, Nikolaus Fortelny, André Rendeiro, Florian Halbritter, Wolfgang Weninger, Thomas Decker, Matthias Farlik, Christoph Bock (8/9)

🗺️ In summary, this study provides a blueprint of epigenetic & transcriptional dynamics and regulator functions underlying macrophage immune responses. We found it particularly useful to combine and integrate multi-omics time-series with high-content CRISPR screening. (7/9)

💡 Biological detail: EP300-mediated repression of interferon-stimulated genes (ISGs), validated genetically & pharmacologically. Proposed mechanism: The histone acetyltransferase EP300 counteracts HDAC activity required for BRD4 availability for transcription elongation. (6/9)

🤖 We used machine learning to infer functional similarity maps of transcriptional regulators from the CROP-seq data, establishing a broadly applicable method to dissect transcriptional programs. (5/9)

✂️ To disentangle causes and consequences, we performed high-content CRISPR screening (CROP-seq + CITE-seq) to perturb 135 regulators during Listeria infection. Our hits include: PU.1, JAK-STAT proteins, splicing factors (SFPQ, SF3B1) & epigenetic regulators (EP300, SMC1A). (4/9)

🧬 Integrative analysis revealed strong differences between interferon-driven (IFN-β/γ) and pathogen-driven (Listeria/LPS) trajectories. Many immune genes showed "epigenetic potential": pre-established open chromatin ready for rapid expression upon stimulation. #Epigenetics (3/9)

🦠 Pathogens & cytokines trigger macrophage receptors and induce immune gene expression. We challenged mouse macrophages (BMDMs) with 6 immune stimuli (Listeria, LCMV, Candida, LPS, IFN-β, IFN-γ) and profiled genes (RNA-seq) and chromatin (ATAC-seq) over six time points. (2/9)

🛡️How do macrophages tailor their defenses to different pathogens? Our new paper in @cp-cellsystems.bsky.social combines dense multi-omics time series with high‐content CRISPR screens (CROP-seq) to map the regulatory landscape underlying macrophage immune responses: www.cell.com/cell-systems... (1/9)

🧬How do #macrophages respond so quickly to pathogens?
A new study by CeMM & @meduniwien.ac.at researchers, led by @bocklab.bsky.social & @mfarlik.bsky.social, reveals key regulators of immune responses using gene editing & machine learning.

➡️ More info: bit.ly/40p5ABe
🔗 Study: bit.ly/4lwEAIm

🤝 Great collaboration between @bocklab.bsky.social (@moritzbaio.bsky.social, Animesh, Jake), @nonchev.bsky.social, @gxxxr.bsky.social, and pathologist Viktor Kölzer.

SpotWhisperer is at #ICML25 FM4LS workshop. Visit our poster on Saturday (19 July 2025) if you're interested & attending ICML. (6/6)

🚀 Next steps: (1) Interactive SpotWhisperer web application; (2) tri-modal joint embedding of spatial transcriptomics, textual annotations, and images; (3) validation across a broad range of histopathological applications. What would you like to see? (5/6)

Molecularly informed analysis of histopathology images using natural language Histopathology refers to the microscopic examination of diseased tissues and routinely guides treatment decisions for cancer and other diseases. Currently, this analysis focuses on morphological featu...

🧑‍💻 In summary, SpotWhisperer integrates spatial transcriptomes into histopathology, bypassing high costs (we infer gene expression from H&E stains) and complexity (we built a chat interface). Check out our preprint: www.biorxiv.org/content/10.1... & website: spotwhisperer.bocklab.org (4/6)

🔍 While vision language models (VLMs) for digital pathology converse about H&E images as a whole, SpotWhisperer provides fine-grained, spot-level resolution. Consequently, SpotWhisperer outperformed SOTA VLMs (PLIP, CONCH) in the prediction of tumor regions and cell types. (3/6)

⚙️ Our SpotWhisperer method predicts spatial transcriptomes from standard H&E images with DeepSpot, and it uses CellWhisperer transcriptome-text embeddings for natural-language conversations about the cells and their transcriptomes. (2/6)

🔬 Toward histopathology 2.0: spatial transcriptomes inferred from routine diagnostic H&E images + a chat interface for cell-resolution histopathology through English language. (1/6)