Integrative analysis of CRISPR screening data uncovers new opportunities for optimizing cancer immunotherapy

Abstract Background In recent years, the application of functional genetic immuno-oncology screens has showcased the striking ability to identify potential regulators engaged in tumor-immune interactions. Although these screens have yielded substantial data, few studies have attempted to systematically aggregate and analyze them. Methods In this study, a comprehensive data collection of tumor immunity-associated functional screens was performed. Large-scale genomic data sets were exploited to conduct integrative analyses. Results We identified 105 regulator genes that could mediate resistance or sensitivity to immune cell-induced tumor elimination. Further analysis identified MON2 as a novel immune-oncology target with considerable therapeutic potential. In addition, based on the 105 genes, a signature named CTIS (CRISPR screening-based tumor-intrinsic immune score) for predicting response to immune checkpoint blockade (ICB) and several immunomodulatory agents with the potential to augment the efficacy of ICB were also determined. Conclusion Overall, our findings provide insights into immune oncology and open up novel opportunities for improving the efficacy of current immunotherapy agents.

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PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade

10.1101/2021.07.28.454202 ◽

2021 ◽

Author(s):

Nivine Srour ◽

Oscar D Villareal ◽

Zhenbao Yu ◽

Samuel Preston ◽

Wilson H. Miller ◽

...

Keyword(s):

T Cell ◽

Tumor Immunity ◽

Immune Checkpoint ◽

Immune Cell ◽

Therapeutic Potential ◽

Immune Checkpoint Blockade ◽

Cell Infiltration ◽

Melanoma Tumor ◽

Cell Immunity

Despite the success of immune checkpoint inhibitor (ICI) therapy in different cancers, resistance and relapses are frequent. Thus, combination therapies are expected to enhance response rates and overcome resistance to ICIs. Herein, we report that combining protein arginine methyltransferase 7 (PRMT7) inhibition with ICIs triggers a strong anti-tumor T cell immunity and restrains tumor growth in vivo by increasing tumor immune cell infiltration. Consistently, TCGA database analysis showed an inverse correlation between PRMT7 expression and T cell infiltration in human melanomas. Mechanistically, we show that PRMT7 has a two-prong effect on melanoma tumor immunity. On one hand, it serves as a coactivator of IRF-1 for PD-L1 expression by upregulating promoter H4R3me2s levels in melanoma cells. Next, PRMT7 prevents repetitive element expression to avoid intracellular dsRNA accumulation or 'viral mimicry'. PRMT7 deletion resulted in increased endogenous retroviral elements (ERVs), dsRNA, and genes implicated in interferon activation, antigen presentation and chemokine signaling. Our findings identify PRMT7 as factor used by melanoma to evade anti-tumor immunity and define the therapeutic potential of PRMT7 alone or in combination with PD-(L)1 blockade to enhance ICI efficiency.

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Faculty Opinions recommendation of Comparative assessment of large-scale data sets of protein-protein interactions.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1006598.82257 ◽

2002 ◽

Author(s):

Rob Russell

Keyword(s):

Protein Interactions ◽

Large Scale ◽

Comparative Assessment ◽

Data Sets ◽

Protein Protein Interactions ◽

Large Scale Data ◽

Scale Data ◽

Large Scale Data Sets

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The Therapeutic Potential of Chemokines in the Treatment of Chemotherapy- Induced Peripheral Neuropathy

Current Drug Targets ◽

10.2174/1389450120666190906153652 ◽

2020 ◽

Vol 21 (3) ◽

pp. 288-301 ◽

Cited By ~ 5

Author(s):

Lin Zhou ◽

Luyao Ao ◽

Yunyi Yan ◽

Wanting Li ◽

Anqi Ye ◽

...

Keyword(s):

Nervous System ◽

Neuropathic Pain ◽

Immune System ◽

Peripheral Neuropathy ◽

Immune Cell ◽

Therapeutic Potential ◽

Chemotherapeutic Agents ◽

Cell Trafficking ◽

Mediated Communication ◽

Novel Therapeutic Strategies

Background: Some of the current challenges and complications of cancer therapy are chemotherapy- induced peripheral neuropathy (CIPN) and the neuropathic pain that are associated with this condition. Many major chemotherapeutic agents can cause neurotoxicity, significantly modulate the immune system and are always accompanied by various adverse effects. Recent evidence suggests that cross-talk occurs between the nervous system and the immune system during treatment with chemotherapeutic agents; thus, an emerging concept is that neuroinflammation is one of the major mechanisms underlying CIPN, as demonstrated by the upregulation of chemokines. Chemokines were originally identified as regulators of peripheral immune cell trafficking, and chemokines are also expressed on neurons and glial cells in the central nervous system. Objective: In this review, we collected evidence demonstrating that chemokines are potential mediators and contributors to pain signalling in CIPN. The expression of chemokines and their receptors, such as CX3CL1/CX3CR1, CCL2/CCR2, CXCL1/CXCR2, CXCL12/CXCR4 and CCL3/CCR5, is altered in the pathological conditions of CIPN, and chemokine receptor antagonists attenuate neuropathic pain behaviour. Conclusion: By understanding the mechanisms of chemokine-mediated communication, we may reveal chemokine targets that can be used as novel therapeutic strategies for the treatment of CIPN.

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Dehydroepiandrosterone (DHEA) and its Sulphate (DHEAS) in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205017666200317092310 ◽

2020 ◽

Vol 17 (2) ◽

pp. 141-157 ◽

Cited By ~ 2

Author(s):

Dubravka S. Strac ◽

Marcela Konjevod ◽

Matea N. Perkovic ◽

Lucija Tudor ◽

Gordana N. Erjavec ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Therapeutic Potential ◽

Relevant Literature ◽

Comprehensive Overview ◽

Brain Functions ◽

Specific Effects ◽

And Behavior

Background: Neurosteroids Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulphate (DHEAS) are involved in many important brain functions, including neuronal plasticity and survival, cognition and behavior, demonstrating preventive and therapeutic potential in different neuropsychiatric and neurodegenerative disorders, including Alzheimer’s disease. Objective: The aim of the article was to provide a comprehensive overview of the literature on the involvement of DHEA and DHEAS in Alzheimer’s disease. Method: PubMed and MEDLINE databases were searched for relevant literature. The articles were selected considering their titles and abstracts. In the selected full texts, lists of references were searched manually for additional articles. Results: We performed a systematic review of the studies investigating the role of DHEA and DHEAS in various in vitro and animal models, as well as in patients with Alzheimer’s disease, and provided a comprehensive discussion on their potential preventive and therapeutic applications. Conclusion: Despite mixed results, the findings of various preclinical studies are generally supportive of the involvement of DHEA and DHEAS in the pathophysiology of Alzheimer’s disease, showing some promise for potential benefits of these neurosteroids in the prevention and treatment. However, so far small clinical trials brought little evidence to support their therapy in AD. Therefore, large-scale human studies are needed to elucidate the specific effects of DHEA and DHEAS and their mechanisms of action, prior to their applications in clinical practice.

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Galaxy spin direction distribution in HST and SDSS show similar large-scale asymmetry

Publications of the Astronomical Society of Australia ◽

10.1017/pasa.2020.46 ◽

2020 ◽

Vol 37 ◽

Author(s):

Lior Shamir

Keyword(s):

Large Scale ◽

Spiral Galaxies ◽

Hubble Space Telescope ◽

Gravitational Interaction ◽

Large Data ◽

Sloan Digital Sky Survey ◽

Data Sets ◽

Dipole Axis ◽

Data Set ◽

The Asymmetry

Abstract Several recent observations using large data sets of galaxies showed non-random distribution of the spin directions of spiral galaxies, even when the galaxies are too far from each other to have gravitational interaction. Here, a data set of $\sim8.7\cdot10^3$ spiral galaxies imaged by Hubble Space Telescope (HST) is used to test and profile a possible asymmetry between galaxy spin directions. The asymmetry between galaxies with opposite spin directions is compared to the asymmetry of galaxies from the Sloan Digital Sky Survey. The two data sets contain different galaxies at different redshift ranges, and each data set was annotated using a different annotation method. The results show that both data sets show a similar asymmetry in the COSMOS field, which is covered by both telescopes. Fitting the asymmetry of the galaxies to cosine dependence shows a dipole axis with probabilities of $\sim2.8\sigma$ and $\sim7.38\sigma$ in HST and SDSS, respectively. The most likely dipole axis identified in the HST galaxies is at $(\alpha=78^{\rm o},\delta=47^{\rm o})$ and is well within the $1\sigma$ error range compared to the location of the most likely dipole axis in the SDSS galaxies with $z>0.15$ , identified at $(\alpha=71^{\rm o},\delta=61^{\rm o})$ .

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Accelerating In-Transit Co-Processing for Scientific Simulations Using Region-Based Data-Driven Analysis

Algorithms ◽

10.3390/a14050154 ◽

2021 ◽

Vol 14 (5) ◽

pp. 154

Author(s):

Marcus Walldén ◽

Masao Okita ◽

Fumihiko Ino ◽

Dimitris Drikakis ◽

Ioannis Kokkinakis

Keyword(s):

Large Scale ◽

Data Driven ◽

Data Sets ◽

Output Constraints ◽

Data Driven Approach ◽

Scientific Simulations ◽

Multiple Metrics ◽

In Transit ◽

Multiple Compression ◽

Large Scale Simulations

Increasing processing capabilities and input/output constraints of supercomputers have increased the use of co-processing approaches, i.e., visualizing and analyzing data sets of simulations on the fly. We present a method that evaluates the importance of different regions of simulation data and a data-driven approach that uses the proposed method to accelerate in-transit co-processing of large-scale simulations. We use the importance metrics to simultaneously employ multiple compression methods on different data regions to accelerate the in-transit co-processing. Our approach strives to adaptively compress data on the fly and uses load balancing to counteract memory imbalances. We demonstrate the method’s efficiency through a fluid mechanics application, a Richtmyer–Meshkov instability simulation, showing how to accelerate the in-transit co-processing of simulations. The results show that the proposed method expeditiously can identify regions of interest, even when using multiple metrics. Our approach achieved a speedup of 1.29× in a lossless scenario. The data decompression time was sped up by 2× compared to using a single compression method uniformly.

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Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade

Nature Communications ◽

10.1038/s41467-021-23731-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sebastian R. Nielsen ◽

Jan E. Strøbech ◽

Edward R. Horton ◽

Rene Jackstadt ◽

Anu Laitala ◽

...

Keyword(s):

Cd8 T Cells ◽

Immune Cell ◽

Immune Checkpoint Blockade ◽

Ductal Adenocarcinoma ◽

Cancer Growth ◽

Cancer Therapies ◽

Cell Type ◽

Clinical Prognosis ◽

Tumor Associated Neutrophils ◽

Poor Clinical Prognosis

AbstractPancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.

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Tissue immune profiles supporting response to mesenchymal stromal cell therapy in acute graft-versus-host disease—a gut feeling

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1449-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Caroline Gavin ◽

Erik Boberg ◽

Lena Von Bahr ◽

Matteo Bottai ◽

Anton Törnqvist Andrén ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Mesenchymal Stromal Cell ◽

Stromal Cell ◽

Immune Cell ◽

Therapeutic Potential ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Cell Profile ◽

Acute Graft

AbstractAcute graft-versus-host disease (aGvHD), post-allogeneic hematopoietic stem cell transplantation, is associated with high mortality rates in patients not responding to standard line care with steroids. Adoptive mesenchymal stromal cell (MSC) therapy has been established in some countries as a second-line treatment.Limitations in our understanding as to MSC mode of action and what segregates patient responders from non-responders to MSC therapy remain. The principal aim of this study was to evaluate the immune cell profile in gut biopsies of patients diagnosed with aGvHD and establish differences in baseline cellular composition between responders and non-responders to subsequent MSC therapy.Our findings indicate that a pro-inflammatory immune profile within the gut at the point of MSC treatment may impede their therapeutic potential. These findings support the need for further validation in a larger cohort of patients and the development of improved biomarkers in predicting responsiveness to MSC therapy.

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Compartment and hub definitions tune metabolic networks for metabolomic interpretations

GigaScience ◽

10.1093/gigascience/giz137 ◽

2020 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

T Cameron Waller ◽

Jordan A Berg ◽

Alexander Lex ◽

Brian E Chapman ◽

Jared Rutter

Keyword(s):

Large Scale ◽

Metabolic Networks ◽

Shortest Paths ◽

Large Data ◽

Differential Regulation ◽

Large Data Sets ◽

Data Sets ◽

Human Metabolism ◽

Experimental Conditions ◽

Systemic Model

Abstract Background Metabolic networks represent all chemical reactions that occur between molecular metabolites in an organism’s cells. They offer biological context in which to integrate, analyze, and interpret omic measurements, but their large scale and extensive connectivity present unique challenges. While it is practical to simplify these networks by placing constraints on compartments and hubs, it is unclear how these simplifications alter the structure of metabolic networks and the interpretation of metabolomic experiments. Results We curated and adapted the latest systemic model of human metabolism and developed customizable tools to define metabolic networks with and without compartmentalization in subcellular organelles and with or without inclusion of prolific metabolite hubs. Compartmentalization made networks larger, less dense, and more modular, whereas hubs made networks larger, more dense, and less modular. When present, these hubs also dominated shortest paths in the network, yet their exclusion exposed the subtler prominence of other metabolites that are typically more relevant to metabolomic experiments. We applied the non-compartmental network without metabolite hubs in a retrospective, exploratory analysis of metabolomic measurements from 5 studies on human tissues. Network clusters identified individual reactions that might experience differential regulation between experimental conditions, several of which were not apparent in the original publications. Conclusions Exclusion of specific metabolite hubs exposes modularity in both compartmental and non-compartmental metabolic networks, improving detection of relevant clusters in omic measurements. Better computational detection of metabolic network clusters in large data sets has potential to identify differential regulation of individual genes, transcripts, and proteins.

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