bluuebunny/crossref_metadata_2025_split huggingface dataset:
Medullary sinus macrophages limit cancer therapy efficacy by an efferocytosis-induced IL-33/ST2 axis in the tumor-draining lymph node
Authors: Lamorte Sara , Neufeld Luke , Quevedo Rene , Zhang Xin , Ciudad M Teresa , Jin Robbie , Saeed Zaid Kamil , Karlsson Mikael C I , Mak Tak W , Munn David , Brooks David , McGaha Tracy 
Published: August 2023

Abstract
Cell death is a fundamental aspect of tissue homeostasis that can expose potentially immunogenic cell components that must be removed to prevent inflammatory autoimmunity. We have shown immune suppression in response to apoptotic cell phagocytosis (a process called efferocytosis) is dependent on tissue-resident macrophages (Mf). Indeed, if we disrupt Mf regulatory responses post-efferocytosis, the same apoptotic cells induce inflammation suggesting Mf responses to dying cells are a key determinant of tolerance. We predict that resident macrophages lining the lymphatic sinus inside the lymph nodes are responsible for tolerance against tumor apoptotic cells. Using our mouse melanoma model, we observed that after either chemotherapy or targeted therapy a subpopulation of macrophages of the TDLN, called medullary sinus Mf (MSM), avidly phagocytosed dying tumor cells and acquired a tolerogenic phenotype. RNA sequencing analysis revealed MSM rapidly and exclusively induced expression of the alarmin IL-33 as opposed to other Mf or dendritic cell populations in the TDLN. Importantly, genetic deletion of Il33 in MSM using a novel MSM-specific deletion model (MSM-IL33ko) generated by our laboratory, or blockade of the IL-33 receptor ST2 with IgG, transformed responses to both chemotherapy or targeted therapy with prolonged, enhanced tumor control and reduced cancer reoccurrence. Functionally, MSM-derived IL-33 triggered accumulation and activation of regulatory T cells in the TDLN which then migrated to the tumor limiting intratumoral CD8+ T cell function. Thus, our data revealed a previously undescribed tumor cell death-induced mechanism limiting anti-cancer immunity and therapy efficacy.
CIHR, NIH
Absence of Toll-like receptor 5 confers survival in mice bearing ovarian tumors treated with anti-PD-L1
Authors: McGinty Mitchell Thomas , Kolli Sree , Putelo Audrey , Feng Tzu-Yu , Rutkowksi Melanie 
Published: August 2023

Abstract
Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system. Patients bearing ovarian tumors infiltrated with high frequencies of T cells associate with a greater survival probability. However, therapies targeting T cells in ovarian cancers are ineffective. We observed in models of late-stage murine ovarian cancer that in absence of Toll-Like Receptor 5 (TLR5) signaling, anti-PD-L1 promotes significant survival and protection against tumor rechallenge. Ovarian tumors from rechallenged TLR5KO mice exhibited significantly higher frequency/number of CD8 T cells expressing functional and activation markers. Thus, in the absence of TLR5 signaling, T cells mount/maintain a stronger response to ovarian tumors after inhibitory receptor blockade. Furthermore, protection against tumor progression in TLR5KO mice corresponds with a significant increase in tumor infiltrating cross presenting and IL-12 producing Dendritic cells (DCs). Additionally, in CD11c Cre x TLR5 fl/fl mice, whose DCs lack TLR5 expression, PD-L1-blockade mediated extended survival in ovarian tumor-bearing mice. Using a mixed bone marrow chimera approach, we demonstrate that direct TLR5 signaling functionally alters DCs to become more suppressive in the tumor microenvironment, impacting T cell differentiation and anti-tumor activity, thereby reducing survival during aPD-L1 therapy. Clinically, roughly 7.5% of the general population harbor a TLR5 SNP that diminishes TLR5 signaling and is associated with increased long-term survival for ovarian cancer patients. Therefore, patients who express the TLR5 SNP may immediately benefit from anti-PDL1 therapy and those without the SNP, TLR5 antagonism.
NIH/NCI 1R01CA253285 UVA Farrow Fellowship
Elucidating the role of heat shock protein receptor CD91 on antigen presenting cells during cancer immunosurveillance
Authors: Nayak Devanshi A , Binder Robert J 
Published: August 2023

Abstract
The premise of immunosurveillance is that the immune system, particularly by T cells, allows detection and elimination of emerging tumor cells. However, the mechanisms that allow efficient T cell priming against nascent tumors despite limited antigen availability remain unclear. We have shown that immunogenic heat shock proteins (HSPs) such as gp96 and their receptor CD91 are one such mechanism. HSPs efficiently chaperone minute levels of peptides from tumors to elicit antigen-specific immunity. Cross presentation of HSP-chaperoned peptides by CD91+ dendritic cells is a key mechanism for priming T cell responses. Diverse DC subsets vary in their capacity to modulate such anti-tumor immune responses. In this project, we aim to understand which CD91+ DC subset(s) is/are important for HSP-mediated cancer immunosurveillance. We generated mouse strains with deletion of CD91 on specific DC subsets. cDC1s are thought to be superior cross-presenters that excel in activation of cytotoxic lymphocytes. CD91 deletion in cDC1 render mice highly susceptible to chemically induced tumors. To better understand the CD91-HSP pathway, we tracked the dispersal of tumor-derived gp96 among myeloid cells using tumor cells that express EGFP-tagged gp96. We show that migratory DC subpopulations, such as CD103+ (cDC1) dendritic cells acquire gp96 from the tumor microenvironment, while a different DC subset (CD11b+ CD11c+) transfers protective antitumor immunity. The hand-off of tumor-derived gp96 between migratory and lymph node resident DCs is currently under investigation. These results advance our understanding of the HSP-CD91 pathway and its role in DC function which can have significant implications for cancer prognosis and therapy.
5R01CA233803-04
Unmasking Arterial-resident Autoreactive B cells involved in Atherosclerosis and Peripheral Artery Disease Progression
Authors: Taylor Joshua A , Gearhart Patricia J , Maul Robert W 
Published: August 2023

Abstract
Atherosclerosis activates the immune system, including B cells which secrete antibodies that bind antigens released by necrotic cells within plaques and may promote inflammation. To identify these antibodies, we isolated activated B cells from atherosclerotic ApoE-deficient mice aortas and human tibial arteries with peripheral artery disease post-amputation. Single-cell sequencing of the B cell receptors identified 35 mouse and 48 human overrepresented disease-relevant heavy and light chain pairings, which were sequentially expressed as antibody. Epitope determination was performed by human proteome array, and 14 mouse and 21 human protein targets were found with significant affinity and specificity. Mouse antigens were scrutinized by immunohistochemistry to confirm presence in inflamed plaques, and expression of these proteins were used to interrogate autoreactive antibody titers in diseased sera by ELISA. ApoE-deficient mice were immunized with the 6 most promising antigens. Serum antibody measurement showed strong, rapid, and early onset of antigen-specific antibody responses in the immunized mice compared to an adjuvant only control group. Strikingly, we saw decreased plaque accumulation in the immunized animals, suggesting antigen responses may clear pathogenic antigens before disease develops. Likewise, human antigen ELISAs comparing antigen-specific serum antibody titers to patient Framingham score for cardiovascular risk supported a role for two antigens in disease. To confirm these antigens as potential biomarkers, we will characterize the emergence of their antibody counterparts using a historical library of serum samples from individuals enrolled in the Baltimore Longitudinal Study on Aging.
This work is directly funded by the National Institutes of Health – National Institute on Aging’s Intramural Research Program in the Lab of Molecular Biology and Immunology
Selective targeting of auto reactive B cells using bispecific molecules
Authors: Griffith Amber Simone , Apley Kyle , Downes Grant , Ross Patrick , Dekosky Brandon , Farrell Mark , Berkland Cory , Kendall Peggy 
Published: August 2023

Abstract
Type 1 diabetes occurs when autoreactive T cells attack insulin-producing cells in pancreatic islets. B cells promote disease by acting as essential antigen presenting cells. Targeted immune therapy for treatment and prevention of autoimmune diseases is preferable to drugs that cause global immunosuppression. We therefore investigated the efficacy of three constructs designed to specifically target and neutralize anti-insulin B cells. Construct one has a 4-arm PEG backbone with insulin attached to 2 of the arms (insulin-PEG). Construct two has insulin attached to 2 of the PEG arms and a trisaccharide molecule that acts as a ligand for inhibitory receptor CD22 on the remaining 2 PEG arms (insulin-PEG-CD22L). Construct three consists of insulin directly conjugated to CD22L (insulin-CD22L). In vitro experiments using transgenic anti-insulin B cells demonstrate that insulin-PEG unexpectedly promotes excessive proliferation and upregulation of CD86 in anti-CD40 treated anti-insulin B cells. Addition of CD22L (insulin-PEG-CD22L) restores anti-insulin B cell responses to baseline but has no overall benefit. Conversely, insulin-CD22L blunts the effects of anti-CD40 stimulation, reducing proliferation by 15% and IgM surface expression by 50% . CD22L alone has no effect on stimulated anti-insulin B cells. Preliminary in vivo data using 2-photon imaging shows that insulin-CD22L binds anti-insulin B cells in spleen, pancreatic lymph nodes and pancreatic islets within 30 minutes of injection. Thus, this novel insulin-CD22L construct directs the dampening effect of CD22 specifically to anti-insulin B cells that promote T1D, making it a promising therapeutic intervention that may also be useful when paired with anti-T cell treatments.
P20GM1133117 T32GM008545 5T32AI7163-43
Pro-resolution lipid mediator maresin-1 reduces inflammation, promotes neuroprotection, and prevents disease progression in multiple sclerosis model of autoimmunity
Authors: Zahoor Insha , Nematullah Mohammad , Mir Sajad , Ahmed Mohammad Ejaz , Rattan Ramandeep , Shailendra Giri 
Published: August 2023

Abstract
Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease in young adults, resulting in neurological defects and disability. The endogenous mechanisms for resolving inflammation are intact but become defective in patients, resulting in a lack of resolution mediators and unresolved inflammation. Because DHA metabolism is impaired in MS, we hypothesize that supplementing its downstream metabolite maresin 1 (MaR1) will alleviate inflammation and demyelination in animal model of MS called experimental allergic encephalomyelitis (EAE). EAE was induced in SJL mice, followed by treatment with MaR1 (300ng, 200ul in PBS/animal/day ip) on day 6 after disease induction. Monitoring the disease course, recall response by ELISA, cytokine expression analysis by qPCR and western blotting, and immune profiling by flow cytometry were used to assess the effect of MaR1 treatment in EAE. The neuroprotective effect of MaR1 was also assessed using single molecule array (SIMOA), histopathology, and IHC. Statistical analysis was done using Graph-Pad Prism. Restoration of MaR1 had a protective effect on neurological deficits, prevented disease progression, and reduced disease severity in EAE by reducing immune cell infiltration (CD4+IL17+ and CD4+IFN+) into the CNS (P&lt;0.001). It significantly reduced the proinflammatory cytokine IL17 (P&lt;0.01) and promoted an anti-inflammatory response via IL10 and IL4 (P&lt;0.001). Furthermore, it exerted neuroprotective effects as evidenced by higher MBP expression in the brain from the MaR1 treated group. Overall, MaR1 supplementation has anti-inflammatory and neuroprotective effects in preclinical animal models, implying that it could be a new therapeutic molecule in MS.
Supported by grants from National Multiple Sclerosis Society (US) Research Grant (RG-2111-38733, RG-1807–31964 and RG-1508– 05912), the US National Institutes of Health Grant (NS112727 and AI144004), and Henry Ford Hospital Internal Grant (A10270 and A30967) to SG.
Amelioration of Collagen-Induced Arthritis in Rats by a Monoclonal Antibody against the Novel Epitope of Cysteine Protease from P. gingivalis
Authors: Tsay Gregory J , Yeh Yung-Ju , Xue Ting-Yin , Peng Hsin-Yi , Hsieh Fei-Hung , Wu Ya-Wun , Chen Shih-Yao , Chen Yeh , Chen Hui-Chen , Chang Han , Tsai Chung-Hao 
Published: August 2023

Abstract

Background
The use of biological diseases-modifying anti-rheumatic drugs (bDAMRD) including anti-tumor necrosis factor-α (TNF-α) has revolutionized the therapy of rheumatoid arthritis (RA). However, approximately 30–40% of patients with RA do not response to anti-TNF therapy when used as the first-line bDMARD.

Objective
The aim of the study is to develop a new, novel monoclonal antibody for the therapy of RA.

Methods
Monoclonal antibody development: BALB/c mice were immunized with OVA-conjugated peptide for CIA. Spleen cells were collected for fusion with myeloma cells. The rats were divided into 6 groups: Normal control, CIA, IgG1(15 mg/kg)-treated CIA, low-mAb (3 mg/kg)-treated CIA, High-mAb (9 mg/kg)-treated CIA, and Enbrel (4.5 mg/kg)-treated CIA.

Results
The monoclonal is only reacted to the immunized peptide and is IgG1 Kappa, high melting temperature with Tm=4.8, High binding to FCγRIIb and FCγR III, and low dissociation constant (Kd=19.6×10−9) of Ag-mAb affinity. The mAb stains mainly on cytoplasm with several coarse discrete dots on SW982 cells. After treatment with this mAb in CIA, the mice have showed dose-dependent effects, improving articular index and ankle circumference, reduced inflammation and synovium proliferation, restored joint space narrowing, and cartilage on immunohistochemistry. The therapeutic results in the mAb-treated group has shown to be excellent in CIA animal RA model.

Conclusion
We’ve generated a novel monoclonal antibody which has excellent therapeutic effects in the therapy of RA animal model. This study is the first time to demonstrate that targeting on the different signal pathway of CIA can have a promising effect on RA therapy.
A KIR x CD8 targeting bispecific modulator enhances regulatory CD8 T cell functions, and reduces inflammation in models of autoimmune disease
Authors: Gardell Jennifer L , Boster Daniel , Bowser Justin , Fasnacht Rachael , Fitzpatrick Kristin , Hermansky Gleda , Julien Susan , Maurer Meghan , McMahan Catherine , Meengs Brent , Patton Daniel , Pham Minh , Therriault Jon , Swiderek Kristine M , Crane Courtney 
Published: August 2023

Abstract

INTRODUCTION
We have characterized a subset of CD8 T cells (CD8 Treg) with immunosuppressive characteristics in inflammatory disease settings. CD8 Treg activation results in their oligoclonal expansion and elimination of pathogenic CD4 T cells. Here we describe a bispecific CD8 Treg modulator that activates autoimmune patient derived CD8 Treg resulting in the cytolytic elimination of pathogenic CD4 T cell in vitro, ex vivo, and in vivo.

METHODS
We tested target and cell binding of a novel bispecific CD8 Treg modulator by Octet and flow cytometry. The functional impact was evaluated using cytotoxicity assays and supernatant analysis in vitro, using Celiac patient derived biopsies ex vivo, and in acute GVHD studies using human PBMCs.

RESULTS
We evaluated the efficacy and mechanism of action of a novel bispecific CD8 Treg modulator directed toward CD8 and inhibitory KIR2DL1/2/3. The modulator enhanced cytolytic CD8 Treg functions in vitro using autoimmune patient PBMCs, increased activated CD4 T cell death, and decreased pro-inflammatory cytokines. In Celiac patient derived duodenal tissues, the modulator increased CD8 Treg prevalence and reduced epithelial cell death after gliadin peptide stimulation. In acute GVHD studies, CD8 Treg modulator treated mice had CD8 Treg expansion in a dose dependent fashion and reduced inflammation.

CONCLUSIONS
A novel KIR x CD8 targeting bispecific modulator restores cytolytic function of CD8 Treg, resulting in a decrease of pathogenic CD4 T cells. We postulate that the bispecific CD8 T cell modulator can reduce autoreactive CD4 T cell prevalence to reestablish immune balance and may represent a selective and broadly applicable therapeutic approach for the treatment of autoimmune disease.
Agonistic anti-PD-1 antibodies downregulate autoantibody development in lupus model mice
Authors: Tokumaru Yosuke , Suzuki Kensuke , Tajima Masaki , Ohkura Iori , Honjo Tasuku , Ohta Akio 
Published: August 2023

Abstract
T follicular helper (Tfh) cells provide B cell help and promote antibody development. Since Tfh cells may be responsible for the development of self-reactive antibodies, this CD4+ T cell subset represent a potential target in the treatment of autoimmune diseases. We have developed anti-PD-1 agonist antibodies that can stimulate the immunosuppressive activity of PD-1. In this study, we sought to inhibit Tfh cells that express PD-1 at high levels and to downregulate antibody production using the PD-1 agonists. PD-1 agonist antibody suppressed IL-21 production from human Tfh-like cells. The co-treatment with PD-1 agonist antibody significantly reduced antigen-specific antibodies in mice immunized with 4-hydroxy-3-nitrophenylacetyl ovalbumin (NP-OVA) and dampened germinal center responses. Chronic GVHD by the transfer of CD8+-depleted splenocytes from C57BL/6 mice into BDF1 mice induces lupus-like symptoms including the induction of autoantibodies and immune complex-mediated nephritis. PD-1 agonist antibody alleviated the induction of anti-dsDNA Ab in the lupus model along with the suppression of germinal center formation. In conclusion, agonistic anti-PD-1 antibodies can effectively prevent autoantibody production and represent unique therapeutic agents in the treatment of autoimmune diseases.
Loss of the MLL3 tumor suppressor accelerates breast tumor onset via HIF1a-induced CCL2-mediated recruitment of CCR2+ regulatory T cells
Authors: Boutet Marie , Erler Piril , Nishitani Kenta , Couturier Nicole , Zhang Zheng , Barbieux Emeline , Guillen Erik , Suzuki Masako , Lauvau Gregoire , Guo Wenjun 
Published: August 2023

Abstract
Understanding how specific cancer mutations modulate the tumor microenvironment is essential for developing new precision cancer therapies. The histone methyltransferase MLL3 is a tumor suppressor that is frequently mutated together with p53 and PI3-kinase in breast cancer. Herein, using a mouse mammary-stem-cell-based tumor model and CRISPR gene editing, we recapitulated this genetic setting and revealed that Mll3 loss promotes tumorigenesis through enhancing tumor-intrinsic aggressiveness and establishing an immunosuppressive microenvironment. Specifically, HIF1a was upregulated in Mll3-mutant tumors and controlled proliferation and stem cell activity of the tumor cells. HIF1a also transcriptionally upregulated expression of the chemokine CCL2 by tumor cells. CCL2 further contributed to rapid CCR2-dependent accumulation of activated, proliferative KLRG1+Foxp3+ regulatory T (Treg) cells at very early stages of tumor initiation, promoting faster tumor onset. These results link MLL3 loss to HIF signaling, CCL2 and Treg cells, and the establishment of an early immune-suppressive microenvironment, a finding that may open new therapeutic opportunities for MLL3-mutant cancers.
Department of Defense Breakthrough awards BC161696 and BC200410
Characterizing the role of IL-33/ST2 axis in regulating anti-tumor function by CD8 T cells during tumor metastasis in the omentum
Authors: Desai Sweta , Meza-Perez Selene , Liu Mingyong , Randall Troy D 
Published: August 2023

Abstract
The omentum, a visceral adipose tissue, is a frequent site of metastasis for gastric and ovarian cancers. Advanced ovarian cancer almost always metastasizes to the omentum. Currently available therapies do not control tumor growth long-term and there is a frequent recurrence of tumor metastasis. In mice, tumor cells injected intraperitoneally implant in the omentum and grow progressively despite tumor-specific CD8 T cells. The lack of effective immunity is due in part, to rapid Treg recruitment in the omentum, which provides an immunosuppressive environment to support tumor growth. The Tregs in the omentum are a specialized population called visceral adipose tissue associated Tregs (VAT-Tregs). A portion of the omental VAT-associated Tregs express ST2, a receptor for Interleukin-33 (IL-33), suggesting that local IL-33 production may contribute to Treg-mediated suppression in the omentum. We also detected persistent, continuously expanding, tumor-specific CD8 T cells in the omentum. Given that IL-33 can also enhance effector function by CD8 T cells and promote their persistence in the presence of chronic antigen stimulation, we are investigating how IL-33 regulates the balance of Treg-mediated immune-suppression and CD8-mediated tumor cell killing in the context of omental adipose tissue.
R01CA216234
PD-L1 couples with LTβR signaling to accelerate regulatory T cell lymphatic migration and tumor metastasis
Authors: Piao Wenji , Wu Long , Pettit Sarah , Bromberg Jonathan S 
Published: August 2023

Abstract

Introduction
Tregs in the tumor environment inhibit anti-tumor immunity and are critical targets for anti-tumor strategies. We previously showed that Tregs use surface lymphotoxin (LTαβ) and PD-1 to signal LTβR and PD-L1 on lymphatic endothelial cells, thereby promoting Treg lymphatic migration. Most tumor cells express LTβR and PD-L1, yet tumor interactions with LTαβ and PD-1 on Tregs are poorly studied. We hypothesized that PD-L1 couples with LTβR signaling on tumors to regulate migration and tumor metastasis.

Methods
Wild type and CRISPR/Cas9 LTβR or PD-L1 knockout B16F10 melanoma were used for signaling and cell migration. Specific LTβR classical and nonclassical NFκB blocking peptides were used.

Results
PD-L1 bound to LTβR in resting B16F10, and blocking LTβR-nonclassical NFκB signaling increased melanoma PD-L1 expression. RNASeq analysis of melanoma revealed that gene expression regulated by LTβR-nonclassical NFκB signaling was increased by PD-L1 depletion, while genes driven by PD-L1 signaling remained unaltered by LTβR depletion. Melanoma cocultured with Tregs had enhanced migration, while combined blockade of PD-L1 and LTβR nonclassical NFκB pathways synergistically blocked tumor migration. In vivo, PD-L1 blockade combined with LTβR classical or nonclassical NFκB blocking peptides inhibited tumor growth and metastases, and enhanced host survival.

Conclusions
PD-L1 couples with LTβR-nonclassical NFκB signaling to regulate tumor growth and migration. Blocking both arms of tumor LTβR-NFκB-signaling enhanced immune checkpoint blockade efficacy and mouse survival. These observations provide a rational strategy to modulate Treg activities to prevent tumor spread.

supported by NIH R37 AI062765 and Emerald grant 2022