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Today, in #preprinthub2 @alisaiakupova.bsky.social @mdc-berlin.bsky.social will present a #preprint from Katya Koltsova lab (Cedars-Sinai Medical Center) on how IL-17RC signaling connects intestinal #microbiota and #neuroimmune interactions in #atherosclerosis 🍔🦠🐭

www.biorxiv.org/content/10.6...

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@cleeterichter.bsky.social will present this preprint today in #preprinthub2! ⚡️🚦🐁 #immunosky @ucsdhealthsci.bsky.social

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Harnessing Inflammatory Monocytes to Overcome Resistance to Anti-PD-1 Immunotherapy Background Resistance to immune checkpoint inhibitors represents a major therapeutic challenge, as less than 50% of patients with melanoma achieve long-term response to immune checkpoint inhibitor therapy. One mechanism of acquired resistance involves somatic mutations, such as loss of beta-2 microglobulin ( B2m ), that enable tumor cells to evade T cell-mediated killing. Methods This study used single-cell RNA-seq, flow cytometry, and ex vivo functional assays to characterize tumor-infiltrating immune cells in antigen presentation-deficient tumors. Tumor-bearing mice were treated with anti-PD-1 or CD40 agonist antibodies and cell depletion or cytokine blocking antibodies to define mechanisms of action. Analysis of published human RNA-seq datasets was performed to dissect the contributions of inflammatory monocytes to patient outcomes. Results We found an increase in immunosuppressive macrophages in B2m -null tumors. We hypothesized that repolarizing myeloid cells may restore control of tumor growth. Treatment with CD40 agonist antibody, which promotes differentiation of monocytes and macrophages towards a proinflammatory phenotype, reduced tumor growth and improved survival in B2m -null melanoma and colorectal cancer models. Unexpectedly, both CD8+ T cells and NK cells, but not CD4+ T cells, were required for the efficacy of CD40 agonist, even though CD8+ T cells cannot directly recognize antigen presentation-deficient tumor cells. Instead, these lymphocytes control tumor growth via secretion of IFNγ, as depletion of IFNγ inhibited the therapeutic effect of CD40 agonist. IFNγ receptor ( Ifngr1 ) expression was required on host cells, not tumor cells, for CD40 agonist-mediated tumor control. Single-cell analysis identified a distinct population of inflammatory monocytes that were enriched for an IFNγ response signature in CD40 agonist-treated tumors, suggesting that these cells may be important for tumor control. Analysis of human bulk and single-cell RNA-seq datasets demonstrated that an inflammatory monocyte signature derived from our data was associated with improved patient outcomes and response to immune checkpoint inhibitors. Conclusions These data demonstrate that CD8+ T cells contribute to tumor control even in the absence of direct antigen presentation by tumor cells. More broadly, our work suggests that strategies to activate the effector functions of inflammatory monocytes may limit tumor growth and overcome acquired resistance to immune checkpoint inhibitors. ### Competing Interest Statement PKS is a co-founder and member of the BOD of Glencoe Software, member of the SAB for RareCyte, Reverb Therapeutics and Montai Health, and consultant for Merck. He holds equity in Glencoe and RareCyte. WNH is an employee and holds equity in Arsenal Biosciences. AHS has patents or pending royalties on the PD-1 pathway from Roche and Novartis. AHS is on advisor boards for Elpiscience, Alixia, Monopteros, GlaxoSmith Kline, Janssen, Amgen, Corner Therapeutics, Bioentre, AltruBio, ImmVue and MabQuest. AHS also is on scientific advisory boards for the Massachusetts General Cancer Center, Program in Cellular and Molecular Medicine at Boston Childrens Hospital, the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, Perlmutter Cancer Center at NYU, the Gladstone Institutes and the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy. She receives research funding from TaiwanBio, unrelated to this paper. She is an academic editor for the Journal of Experimental Medicine. BCM has consulted for Cellarity, LifeOmic, and Telix Pharmaceuticals. * B2m : beta-2 microglobulin MHC-I : major histocompatibility complex I TNF : tumor necrosis factor TAM : tumor-associated macrophage IFN : interferon LPS : lipopolysaccharide agCD40 : CD40 agonist scRNAseq : single-cell RNA-sequencing TME : tumor microenvironment TIL : tumor-infiltrating lymphocyte National Institute of General Medical Sciences, https://ror.org/04q48ey07, T32 GM133364, T32 GM007753 National Cancer Institute, K08CA248960 Burroughs Wellcome Fund, https://ror.org/01d35cw23, CAMS Gene Lay Institute Ludwig Center at Harvard The Mark Foundation for Cancer Research, https://ror.org/00v7th354, ASPIRE award American Cancer Society, https://ror.org/02e463172, Research Scholar Grant PF-24-1316850-01-CD

Tomorrow, in #preprinthub2 Teresa @cemm.oeaw.ac.at will present a preprint from Brian Miller’s lab on how inflammatory #monocytes can be harnessed to overcome resistance to #anti-PD-1 #immunotherapy 🐁🚧🛑

www.biorxiv.org/content/10.6...

#immunosky

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Tomorrow, in #preprinthub2 @alisaiakupova.bsky.social will present a preprint from Xuyu Zhou’s lab on how #TCR signal strength determines #Treg instability and discrimination of self versus non-self antigens 🐁 ⏳🌪️ #immunosky

www.biorxiv.org/content/10.6...

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Today in #preprinthub2 Julia Eder @cemm.oeaw.ac.at will present a #preprint on how #singlecell immunophenotyping identifies CD8+ GZMK+ IFNG+ T cells as a key immune population in cutaneous Lyme disease 👋👾🩸

www.biorxiv.org/content/10.1...

#immunosky #medsky

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Today at #PreprintHub2, Elisa Sánchez from Universidad Autónoma de Madrid will present the preprint by @alexaweingarden.bsky.social, “Gut microbial composition modulates food-specific CD4+ T cells in food allergy” from the Marc K. Jenkins lab 🥜🤒❌

www.biorxiv.org/content/10.1...

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Today at #PreprintHub2, John (Virginia) will present Dufies’ preprint, “Chronic sensing of host-derived lipids is an all-in-one signal that primes and activates NLRP3,” from the @lozanzi.bsky.social lab. 💯✅

www.biorxiv.org/content/10.1...

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O-GlcNAcylation drives macrophage IL-4 responsiveness and tissue residency through metabolic and cell cycle calibration The metabolic requirements for macrophage IL-4 polarization remain contentious, while immunometabolic studies of tissue resident macrophages are still sparse. Hexosamine biosynthesis has gained attention regarding its immune regulatory potential via downstream O-GlcNAcylation. Here we identify protein O-GlcNAcylation as a requirement for IL-4 polarization in vitro and proliferative expansion in vivo during cytokine challenge or infection. We further show that O-GlcNAcylation is critical for controlling tissue residency. By enforcing metabolic and cell cycle quiescence during differentiation, O-GlcNAcylation is needed for adult monocytes to establish a long-live residency program. In this context, its absence leads to perpetual DNA vulnerability and damage via reactive oxygen species, resulting in a senescent-like state poised for cell death. Conversely, long-lived populations instead require O-GlcNAcylation for self-renewal and inflammatory expansion. Our findings altogether suggest O-GlcNAcylation, fueled by hexosamine biosynthesis, serves as a central metabolic rheostat for resident macrophage formation and maintenance during homeostasis and disease. ### Competing Interest Statement The authors have declared no competing interest. Dutch Research Council, https://ror.org/04jsz6e67, 91614087 Wellcome Trust, 219530 Taighde Éireann - Research Ireland, https://ror.org/010t7sr36, 22/PATH-S/10649

Today at #PreprintHub2, Amitava from Vienna will present graham.heieis@bsky.social ’s preprint, “O-GlcNAcylation drives macrophage IL-4 responsiveness and tissue residency through metabolic and cell cycle calibration”, from the Bart Everts lab 💯✅

www.biorxiv.org/content/10.6...

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Chronic alcohol consumption drives inflammaging and transposon derepression in hematopoietic stem and progenitor cells Chronic alcohol use causes pancytopenia and diminished immune responses against pathogens. However, it remains unclear whether chronic alcohol consumption directly induces inflammation in human hemato...

Today at #PreprintHub2, Mariia from Berlin will present
@ridzkytransposon.bsky.social ’s preprint, ‘Chronic alcohol consumption drives inflammaging and transposon derepression in hematopoietic stem and progenitor cells’, from the Dr. Moonjung Jung 's lab 🫗🍸

www.biorxiv.org/content/10.6...

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Systematic Discovery of Pathogen Effector Functions across Human Pathogens and Pathways Pathogens deploy effector proteins to exploit host cell biology, and most pathogen open reading frames (ORFs) are rapidly evolving and lack functional annotation. We developed the eORFeome, a scalable...

Today at #preprinthub2, Freya from Vienna will present
Tomas Pachano and He Leng’s preprint “Systematic Discovery of Pathogen Effector Functions across Human Pathogens and Pathways”, from the labs coordinated by @alex-stark.bsky.social and @miketilapia.bsky.social

www.biorxiv.org/content/10.1...

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CD4 memory T cells orchestrate therapy-responsive immune niches in colorectal cancer liver metastases Colorectal cancer frequently progresses to liver metastases (CRLM), a stage with limited treatment options and poor prognosis. Neoadjuvant chemotherapy is used to control tumor growth and enable resec...

Today at #preprinthub2, Maria and Öykü from Vienna will present Maud Mayoux's preprint “CD4 memory T cells orchestrate therapy-responsive immune niches in colorectal cancer liver metastases” from the labs of Dr. Sonia Tugues and Dr. Bettina Sobottka 💯✅

www.biorxiv.org/content/10.1...

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Today at #PreprintHub2, Felix and Joel from the Medical University of Vienna will present a #preprint by Jake N. Lichterman from Professor Koh’s lab, titled “Timing of immune checkpoint blockade shapes anti-tumor immunity via a clock-dependent chemokine axis.” 🧫🧪

www.biorxiv.org/content/10.1...

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IFNAR1⁺ Neutrophils Orchestrate Chronic Inflammatory Damage Through Mitochondrial Remodeling Neutrophils are abundant innate effector cells that drive mucosal inflammation, yet the mechanisms by which they contribute to chronic inflammatory diseases across distinct tissues remain incompletely...

Today at #PreprintHub2, Meredith from Virginia will present a #preprint by Cecilia Pessoa Rodrigues from the Daniel Regan-Komito Lab, with the title "IFNAR1⁺ Neutrophils Orchestrate Chronic Inflammatory Damage Through Mitochondrial Remodeling" 🔬🧬

www.biorxiv.org/content/10.1...

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Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours CD8+ T cells are a key weapon in the therapeutic armamentarium against cancer. While CD8+CD103+ T cells with a tissue-resident memory T (TRM) cell phenotype have been favourably correlated with patien...

Tomorrow at #PreprintHub2, @lmgail.bsky.social from @cemm.oeaw.ac.at and Lea Heinzl from Uni Wien/MUW will present a #preprint by Thomas N. Burn from Professor Laura Mackay Lab: "Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours"

www.biorxiv.org/content/10.1...

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Tomorrow at #PreprintHub2, Raisa Brito from @mdc-berlin.bsky.social will present a #preprint by Prof. Dr. Karsten Kretschmer titled “Functional Dichotomy of Developmental Foxp3+ Treg Cell Subsets in the Visceral Adipose Tissue of Lean and Obese Mice”

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Type I interferon signaling instills divergent metastatic phenotypes and immunotherapy responses Metastatic colonization of distant tissues is responsible for most cancer deaths, yet while this colonization is typically preceded by lymph node (LN) metastasis, the clonal and functional relationshi...

Today at #PreprintHub2, Teresa Neuwirth from

@cemm.oeaw.ac.at will present a #preprint by

@retickerflynn.bsky.social on how Type I interferon signaling drives divergent metastatic phenotypes and immunotherapy responses 🧬🔬
www.biorxiv.org/content/10.1...

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RORγt+ APCs require a distinct cis-regulatory element to instruct tolerance to dietary antigens Oral tolerance represents a hallmark of intestinal mucosal immunity to prevent inflammatory responses to harmless natural antigens, such as dietary components or commensal organisms. However, the unde...

Tomorrow in #PreprintHub2,
@alisaiakupova.bsky.social from
‪@mdc-berlin.bsky.social‬ will present a #preprint on tolerance to dietary antigens from the Xiaohuan Guo lab 🧬📷
Preprint: www.researchsquare.com/article/rs-4...

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Human chronic inflammation is orchestrated by spatially restricted inflammation-activated Dendritic cells Dendritic cells (DCs) form coordinated networks that orchestrate inflammatory responses across tissues. Upon activation, conventional dendritic cells (DCs) undergo changes in their transcriptome, phen...

This semester’s #preprinthub2 club, led by Carolina Mangana & Alex Deltedesco has concluded with a #preprint on how human chronic inflammation is orchestrated by spatially restricted inflammation-activated #DCs. 🎻🫨🚧 #immunosky

www.biorxiv.org/content/10.1...

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Today, in #preprinthub2 Amitava Sinha will present a #preprint from Angelo lab @stanfordmedicine.bsky.social on how the immunometabolic topography of TB granulomas governs cellular organization and bacterial control. 🦠🚦🙊 #immunosky

www.biorxiv.org/content/10.1...

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Today, in #preprinthub2 @cleeterichter.bsky.social will lead a discussion of a #preprint from @santoshvardhana.bsky.social @mskcancercenter.bsky.social on MEK-dependent bioenergetic demand driving terminal CD8+ T cell exhaustion. 🫩🍰💥 #immunosky

www.biorxiv.org/content/10.1...

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VH-replacement shapes the antibody repertoire by targeting non-pairing heavy-chains The diversity of antibodies underpins robust immune responses. During the formation of the antibody repertoire in early bone marrow B-cells, random antibody heavy-chain proteins are generated from rec...

Today, in #preprinthub2 Palina @viennabiocenter.bsky.social will present a #preprint from Harry N. White & @annecorcoran.bsky.social @babrahaminst.bsky.social on how VH-replacement shapes the antibody repertoire by targeting non-pairing heavy-chains. 🔎🪢🐁

www.biorxiv.org/content/10.1...

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Cutaneous lupus features specialized stromal niches and altered retroelement expression Cutaneous Lupus is an inflammatory skin disease causing highly morbid inflamed skin and hair loss. In order to investigate the pathophysiology of cutaneous lupus, we performed single-cell RNA and spat...

Today, in #preprinthub2 Sarah Wideman will present a #preprint from @virusesimmunity.bsky.social about cutaneous #lupus featuring specialized stromal niches and altered retroelement expression. 🤲🏻🐺🦠

www.biorxiv.org/content/10.1...

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Caspase-1 self-terminates protease activity to enforce homeostasis and prevent inflammasome-driven diseases Signal shutdown mechanisms must exist to silence the potent inflammatory programs initiated by the caspase-1 (CASP1) protease, to allow inflammation to resolve and reinstate tissue homeostasis. It is ...

Today, in #preprinthub2 Raisa Brito @mdc-berlin.bsky.social will present a #preprint from @inflammasomelab.bsky.social on how caspase-1 self-terminates protease activity to enforce homeostasis and prevent #inflammasome driven diseases.
✂️🧯🐭 #immunosky

www.biorxiv.org/content/10.1...

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T cells promote distinct transcriptional programs of cutaneous inflammatory disease in keratinocytes and dermal fibroblasts T cells and structural cells coordinate appropriate inflammatory responses and restoration of barrier integrity following insult. Dysfunctional T cells precipitate skin pathology occurring alongside a...

Today, in #preprinthub2 Kveta will discuss a #preprint from Peter Morawski lab @benaroyaresearch.bsky.social about how T cells promote distinct transcriptional programs of cutaneous inflammatory disease in #keratinocytes and dermal fibroblasts.🖖🕹️📱 #immunosky

www.biorxiv.org/content/10.1...

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B cell repertoire of children with atopic dermatitis exhibit altered IgE maturation associated with allergic food sensitization IgE B cells produce antibodies responsible for the inappropriate specificity seen in allergic disease. In this study, we sequence antibody gene repertoires from a large, well-characterized early life ...

Today in #preprinthub2 @alisaiakupova.bsky.social will discuss a #preprint from @krishnaroskin.bsky.social @cincyresearch.bsky.social on how B cell repertoire of children with AD exhibits altered #IgE maturation associated with allergic food sensitization. 🥜🐕👶
#medsky
www.biorxiv.org/content/10.1...

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A conserved immune dysregulation is associated with infection severity, risk factors prior to infection, and treatment response Older age, being male, obesity, smoking, and comorbidities (e.g., diabetes, asthma) are associated with the increased risk for severe infections. We hypothesized that there is a conserved common immune dysregulation across these risk factors. We integrated single cell and bulk transcriptomic data and proteomic data from 12,026 blood samples across 68 cohorts to test this hypothesis. We found that our previously described 42-gene Severe-or-Mild (SoM) signature, is associated with each of these risk factors prior to infection. Furthermore, we found this conserved immune signature is modifiable using immunomodulatory drugs and lifestyle changes. The SoM score predicted patients with sepsis that would be harmed from hydrocortisone treatment, and patients with asthma that will not respond to monoclonal antibody treatment. Finally, the SoM score was associated with all-cause mortality. The SoM signature has the potential to redefine the immunologic framing of baseline immune state and response to chronic, subacute, and acute illnesses. ### Competing Interest Statement Purvesh Khatri is a co-founder of, consultant to, and a scientific advisor to Inflammatix, Inc. All other authors have nothing to declare. This work has been disclosed through Stanford's Office of Technology and Licensing.

Today Magdalena & @chiralmolecule.bsky.social #preprinthub2 will present a preprint from @stanfordmedicine.bsky.social on how conserved immune dysregulation is associated with #infection severity, risk factors prior to infection, and treatment response 📱🦠🤧 #immunosky
www.biorxiv.org/content/10.1...

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first #preprinthub2 review in @natrevimmunol.bsky.social ⚡️

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The phagosome-mediated anti-bacterial immunity is governed by the proton-activated chloride channel in peritoneal macrophages Phagosome degradation is an evolutionally conserved and highly effective innate immune response against pathogen infections. The success of this process relies on the ability of phagocytes to regulate...

Today in #preprinthub2 John Duncan will present a #preprint from @zhaozhuqiu.bsky.social lab @hopkinsmedicine.bsky.social on how phagosome-mediated anti-bacterial immunity is governed by the proton-activated chloride channel in peritoneal #macrophages 🧯🦠🐭

#immunosky

www.biorxiv.org/content/10.1...

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Likely circulation of a coronavirus in roe deer (Capreolus capreolus) populations suggested by SARS-CoV-2 serological investigation in France The risk of viral transmissions from domestic and wild animals to humans is of high concern for human health. Humans can also transmit viral infections back to domestic and wild animals, which can the...

Today in #preprinthub2 Dominik Kugler will present a #preprint on #coronavirus circulation in roe deer (Capreolus capreolus) populations suggested by #SARSCoV2 serological investigation in France 🦌🇫🇷🦠 #virosky

www.biorxiv.org/content/10.1...

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Poxvirus attack of anti-viral defense pathways unleashes an effector-triggered NF-κB response Effector-triggered immunity (ETI) is a form of pathogen sensing that involves detection of pathogen-encoded virulence factors or 'effectors'. To discover novel ETI pathways in mammals, we developed a ...

Today in #preprinthub2 Lisabeth Pimenov will present a #preprint from Russell Vance & Moritz Gaidt on how a #poxvirus attack of anti-viral defense pathways unleashes an effector-triggered #NFκB response 🦠🚨🥷🏻

www.biorxiv.org/content/10.1...

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