bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-biased immunogenicity of a mucosal subunit vaccine against SARS-CoV-2 in mice
Authors: Li Jianping , Hsu Kevin , Hoang Tanya , XIA ZHENG , SUI YONGJUN , Berzofsky Jay 
Published: November 2024

Abstract
Current vaccines against COVID-19 administered via parenteral route have limited ability to induce mucosal immunity. There is a need for an effective mucosal vaccine to combat SARS-CoV-2 virus replication in the respiratory mucosa. Moreover, sex differences are known to affect systemic antibody responses against vaccines. However, their role in mucosal cellular responses against a vaccine remains unclear and is underappreciated. We evaluated the mucosal immunogenicity of a booster vaccine regimen that is recombinant protein-based and administered intranasally in mice to explore sex differences in mucosal humoral and cellular responses. Our results showed that vaccinated mice elicited strong systemic antibody (Ab), nasal, and bronchiole alveolar lavage (BAL) IgA responses, and local T cell immune responses in the lung in a sex-biased manner irrespective of mouse genetic background. Monocytes, alveolar macrophages, and CD103+ resident dendritic cells in the lungs are correlated with robust mucosal Ab and T cell responses induced by the mucosal vaccine. Our findings provide novel insights into optimizing next-generation booster vaccines against SARS-CoV-2 by inducing spike-specific lung T cell responses, and a rationale for considering biological sex differences in future vaccine research and vaccination practice.
Interrogating the CD47-SIRP axis in chronic T cell stimulation for the translation of Graft-vs.-Host disease therapeutics.
Authors: Wallisch Patrick , Bourne Christopher , Pierre Stephanie , Kurtz Keifer , Scheinberg David 
Published: November 2024

Abstract
Graft-vs.-Host disease (GvHD) is the major complication associated with hematopoietic stem cell transplants (HSCTs), characterized by severe alloreactive immunotoxicity of the graft towards the immunocompromised patient. GvHD affects 40-50% of HSCT patients with an average 3-year survival of just 43%, underlining the need for novel therapies.
CD47 the 'don't-eat-me' signal, interacts with Signal Regulatory Protein alpha (SIRPa), an inhibitory transmembrane receptor on macrophages, preventing the phagocytosis of the target cell. In cancer therapy, CD47-blockers are investigated as novel immunotherapies promoting phagocytosis of cancer cells. Serendipitously, we found that either CD47 blockade or pan-SIRP blockade effectively alleviates GvHD onset in a murine xeno-GvHD model. Early phagocytosis in vivo was found not to be the driver of GvHD alleviation, leading us to investigate SIRP proteins as potential regulators of chronic T cell stimulation. Particularly SIRP gamma (SIRPg) is exclusively expressed on T cells, and is known to be the only other SIRP to ligate CD47, however it is regarded understudied and its function, signaling, its regulators and downstream effectors are not known. In this work we could show that SIRPg is upregulated in a setting of chronic T cell stimulation, that its expression levels correlate with exhaustion marker expression in clinical scRNA seq data sets, and that primary human SIRPg KO T cells show a delayed onset of GvHD similar to SIRP blockade.
SIGLEC-3 (CD33) serves as an effective target in tumor progression
Authors: Lin Yi-Jyun , Sung Pei-Shan , Hsieh Shie-Liang 
Published: November 2024

Abstract
Human CD33 (Siglec-3) possesses an immune-receptor tyrosine-based inhibition motif (ITIM), which recruits Src homology 2 (SH2) containing phosphatases (SHP-1/2) and inositol phosphatase (SHIP) and exerts inhibitory effects. The structure and downstream signaling of CD33 bear similarity to programmed cell death protein-1 (PD-1), a promising target in cancer immune therapy. Previous studies indicate that CD33 serves as a therapeutic target in acute myeloid leukemia (AML), additionally, CD33 also acts as a prevalent surface marker of human myeloid-derived suppressor cells (MDSCs). According to the inhibitory signaling upon CD33 activation, CD33 may participate in tumor progression and the regulatory role of CD33 in solid tumors is still unclear. To investigate whether CD33 influences cancer progression, we established a melanoma tumor (B16F10) mouse model in monocyte/macrophage-specific human CD33 transgenic mice (hCD33 Tg mice, Cx3cr1cre/-hCD33M+/-). Compared to wild-type mice (WT), tumor growth and mortality were larger and higher in CD33 Tg mice. Moreover, an antagonistic anti-hCD33 monoclonal antibody (clone 4L3-46) treatment successfully attenuated tumor growth in hCD33 Tg mice and led to a restructuring of the infiltrating MDSCs population. These results indicate that human CD33 contributes to the advancement of tumors, and the blockade of CD33 represents a promising strategy in tumor therapy.
Human implantable tertiary lymphoid organs (TLO) for solid tumor therapy: from organ chips to the clinic?
Authors: Goyal Girija , Barck Lucas , Zhai Yunhao , Prabhala Pranav , Paudel Sudip , Ku Min Wen , Patil Aditya , Isaacs Abdul , Ingber Donald 
Published: November 2024

Abstract
We previously created an in vitro human TLO model from patient-derived, circulating immune cells using organ-on-a-chip devices and 3D culture in extracellular matrix (ECM). B cells in these TLOs express activation induced cytidine deaminase, which is only expressed in lymphoid tissues and is required for class switching and somatic hypermutation (SHM). When challenged by vaccines, these TLO undergo SHM and produce antigen-specific antibodies and CD8 T cells. To model cancer associated TLOs, we integrated human pancreatic and lung cancer cell lines into these TLO Chips to understand how the immune context of hot and cold tumors differentially impacts TLO formation. The high PDL1/L2 expressing lung cancer cell line that displayed a “hot” phenotype in published murine studies induced high levels of cytokines and stimulated increased TLO formation in the lymphoid Organ Chip. In contrast, the cold, low PDL1/L2 expressing lung and pancreatic cell lines did not induce this cytokine signature or TLO formation. Importantly, TLO assembly correlated with increased B cell activation, anti-tumor CD8 activity, and tumor cell death. When the same mix of immune cells and ECM was injected in humanized mice bearing subcutaneous tumors from the hot lung cancer cell line, new lymphoid tissue containing dense aggregates of T and B cells was induced, showing for the first time that direct injection of synthetic TLOs at the tumor site may offer an alternative form of therapy for solid tumors.
Longitudinal assessment of humoral immune response against SARS-CoV-2 in solid cancer patients: Implications for vaccination strategies
Authors: Oh Ji Eun , Lee Eunjin , Lee Ki Seong 
Published: November 2024

Abstract
In the face of evolving SARS-CoV-2 variants, immunocompromised patients, particularly those with solid cancers, pose unique challenges in vaccine responsiveness. We investigated the humoral immune responses in solid cancer patients (n=64) undergoing anti-cancer treatments, comparing them to healthcare workers (n=23). Over 12 months, we tracked SARS-CoV-2 spike (S) and receptor binding domain (RBD) specific antibodies, memory B cells, and circulating follicular helper T cells (cTfh) post two to five doses of monovalent or bivalent vaccinations and after Omicron variant breakthrough infections (BTI). After the third vaccination, solid cancer patients exhibited antibody levels against wild-type and variants similar to healthy controls. Notably, post-BTI, these patients showed heightened and sustained antibody responses, indicating the efficacy of hybrid immunity. S-specific memory B cells initially mirrored healthy individuals after the third dose but declined faster. The fourth dose had minimal impact, while the fifth significantly boosted classical memory B cells. Post-BTI, durable S-specific memory B cells increased, irrespective of prior vaccination doses. Our findings highlight the resilient and prolonged humoral immunity induced by repeated vaccinations and BTIs in solid cancer patients, offering critical insights for tailored vaccination strategies in immunocompromised populations.
B cell regulation of CD8 T cell phenotype in vaccination and homeostasis
Authors: Manes Cammy , Guerrero-Moreno Miguel , Getahun Andrew , Kedl Ross , Klarquist Jared 
Published: November 2024

Abstract
We have found that B cells are responsible for shaping the phenotype of naïve, effector, and memory CD8 T cells. In MD4 mice, which have a fixed BCR repertoire, we find that naïve T cells exhibit an activated/effector phenotype. This is marked by relatively high pAkt, p70-s6K, and 4e-bp1, as well as low Foxo1 and Eomes. Subunit vaccination in MD4 or B cell-depleted mice leads to a CD8 T cell response that is reduced in numbers and is effector-skewed. Additionally, adoptive transfer of CD8 T cells from C57BL/6 WT mice into MD4 mice demonstrate similar reduction in primary CD8 T cell numbers and effector phenotype upon vaccination, indicating the resulting phenotype is mostly dependent the recipient environment. In contrast, the naïve CD8 T cell development is dependent on the B cell environment where they develop, where we recovered on average 10 times more cells from a WT donor than an MD4 donor. Upon looking at memory formation in a B cell-deficient environment, there is impairment in the MD4 mice. Primary response by CD8 T cells is of the same magnitude in WT and B cell-depleted mice, but effector skewing is still prevalent with observed reductions in CD127+ memory cells. These data indicate B cells play an essential role in the establishment of not only the naïve CD8 T cells repertoire, but additionally the regulation of CD8 T cell phenotypes following subunit vaccination or infection.
Unique immune cells in oral cavity are critical for enteric virus pathogenesis
Authors: Brogden Graham , Labayo Hannah , Salazar Emanuel , Atyeo Natalie , Gribonika Inta , Belkaid Yasmine , Chiorini John , Altan-Bonnet Gregoire , Altan-Bonnet Nihal 
Published: November 2024

Abstract
We recently discovered that salivary glands are a major site of norovirus replication and oral-oral transmission is facilitated by saliva1. However, the cell types infected and the role of saliva in virus dissemination remains to be elucidated. Mice inoculated with norovirus were sampled and cells sorted into immune and epithelial cells. Mice became positive for virus in salivary glands and intestine plus associated lymphatic tissues. The majority of virus was present and replicating in CD45+ immune cells and EpCAM+ epithelial cells. Spatio-temporal analysis of the infection revealed that the earliest and highest viral pools were associated with the mandibular lymph nodes. Furthermore, a unique population of immune cells contained the highest concentration of virus, suggesting that these cells potentially play a sentinel role in disseminating norovirus. Notably, enteric infection of the intestine resulted in high levels of inflammation and cell death, however this was absent in the salivary glands, suggesting a level of immune modulation. Our findings suggest that the immune response in the salivary glands is different from that seen in the intestinal tract, and there is a unique population of immune cells which potentially plays an important role during the infection.
1 Ghosh S, et al. Enteric viruses replicate in salivary glands and infect through saliva. Nature. 2022; 607:345–350. doi: 10.1038/s41586-022-04895-8.
CD8 T cells with an exhaustion-like phenotype remain highly functional in hematologic tumors
Authors: Minnie Simone , Waltner Olivia , Zhang Ping , Takahashi Shuichiro , Nemychenkov Nicole , Ensbey Kathleen , Legg Samuel , Comstock Melissa , Boiko Julie , Bhise Shruti , Wilkens Alec , Koyama Motoko , Dhodapkar Madhav , Chesi Marta , Riddell Stanley , Green Damian , Spencer Andrew 
Published: November 2024

Abstract
Loss of immunosurveillance in solid tumors is associated with CD8 T cell dysfunction/exhaustion (TEX). Immunotherapies target TEX differentiation, which may be modified by differences in microenvironments across cancer types and tissue sites. We characterized TEX differentiation in bone marrow (BM), where liquid tumors reside, using mouse models of myeloma and B cell leukemia progressing after autologous stem cell transplantation and CD19-directed CAR T cells respectively. We used flow cytometry and concurrent analysis of RNA expression and DNA accessibility in single cells. We identified a novel CD8 T cell subset with a terminally exhausted phenotype that retained functional capacity, including secretion of cytotoxic molecules and IFNγ. These cells are referred to as interferon-Gamma-secreting, Phenotypically Exhausted (TG-PhEX). Expression of functional genes in TG-PhEX correlated with Batf expression and accessibility within the BATF motif. Chromatin remodeling in stemness associated genes indicated a loss of self-renewal capacity. Indeed, disease progression was associated with a lack of TG-PhEX expansion and not dysfunction as TG-PhEX effectively killed myeloma with comparable activity to CX3CR1+ TEX. Importantly, we observed analogous cells in myeloma and lymphoma patients. TG-PhEX are a clinically relevant target for immunotherapy of hematologic cancers and demonstrate differences in TEX differentiation across tumor sites and cancer subtypes.
Heterogeneity in tumor-intrinsic sensitivity to interferon gamma stimulation
Authors: Merritt Elliot , Granados Genesis Lara , Monga Isha , Carvallo-Fleming Julie-Ann , Pham Giang , Sritharan Ramja , Farias Richard , Zuluaga Laura , Sia Daniela , Sfakianos John , Badani Ketan , Horowitz Amir , Hirsch Fred , Brody Rachel , Tsankov Alexander , Hopkins Benjamin , Tocheva Anna 
Published: November 2024

Abstract
Interferon gamma (IFNg) drives resistance to PD1-targeting immunotherapies by altering the tumor-intrinsic immune phenome associated with the upregulation of inhibitory ligands and immunosuppressive mediators. Major bottleneck to improving the efficacy of IFNg-inducing immunotherapies is our lack of knowledge as it pertains to tumor-intrinsic features that drive tumor-specific differences in IFNg sensitivity. There is a critical need to define the cellular and molecular mechanisms underlying tumor-intrinsic sensitivity to IFNg in pre-clinical models that reproduce the oncogenic programs of human tumors.
We leveraged patient-derived tumor organoids (PDO) with high-dimensional immunophenotyping and RNA-sequencing to determine IFNg sensitivity across different tumors. Our approach identified significant differences in IFNg sensitivity between malignant cells of the same tumor associated with the expression of therapeutically relevant immune checkpoints and secreted proteins. These differences were driven by unique malignant programs underlying patient-specific intratumoral divergence in IFNg sensitivity.
PDO model intra-tumoral and inter-patient heterogeneity in IFNg sensitivity. This is the first study to reveal how the underlying oncogenic pathways intersect with sensitivity to IFNg stimulation and uncover the breadth of IFNg-induced molecular programs in patient tumors.
FOXP1 and KLF2 Modulate the Transition from Stem-like to Effector in CAR T Cell
Authors: Zhu Ziang , Wu Tuoqi , Yao Chen 
Published: November 2024

Abstract
T cells are a pivotal component of the immune system in combating infections and cancer. In cancer, the presence of self-renewing, stem-like CD8+ T cell subpopulation is crucial for limiting tumor growth and providing sustained immunity. However, prolonged antigen stimulation can induce differentiation of some CD8+ T cells into exhausted T cells, characterized by a loss of self-renewing capacity, impaired function and upregulation of immune checkpoints. Exhaustion poses challenges for CAR-T therapy efficacy. Transcription factors are central to the control of T cell differentiation. Utilizing scATAC+RNA-seq analysis of CAR-T cells, we identified transcriptional regulators of CAR-T cell differentiation. FOXP1, a central element in the stem-like gene regulatory network, facilitates the expansion and preservation of stemness in CAR T cells while restraining excessive effector differentiation. In addition, transcription factor KLF2 plays a key role in promoting the differentiation of effector CAR CD8+ T cells while averting their terminal exhaustion. Thus, our study has demonstrated FOXP1 and KLF2 as crucial regulators of CAR T cells and highlighted their potential as targets for enhancing effectiveness and longevity of CAR T cells in cancer immunotherapy.
COMPOUND 2 is a first-in-class small molecule cGAMP competitive oral STING antagonist that reduces neuroinflammation in mouse models
Authors: Banerjee Monali , Shrivastava Ritesh , Middya Sandip , Basu Sourav , Middya Anindita , Shinde Vaibhav , Ghosh Rajib , Padaliya Manisha , Bano Shahnaj , Mansuri Rubeena , Sharma Priti , Roy Sneha , Soram Thanilsana , Yadav Dharmendra , Puniya Kavita , Gautam Anuj , Pryde David 
Published: November 2024

Abstract
Background: Aberrant activation of the cGAS/STING pathway has been implicated in chronic inflammatory conditions such as neuroinflammation. Emerging evidence reveals that the cGAS-STING-mediated Type I interferon (IFN) signaling axis contributes to neuroinflammation and dopaminergic neurodegeneration in Parkinson's Disease (PD). COMPOUND 2 is a novel cGAMP competitive synthetic small molecule STING antagonist discovered at Curadev. Materials and Methods: Competitive binding was established using radioligand binding assays. The neuroprotective effects of COMPOUND 2 were demonstrated in MPTP treated mice. PK and plasma to brain partitioning of COMPOUND 2 was estimated after oral dosing in mice. Results: COMPOUND 2 inhibits the binding of cGAMP to STING and causes reductions in the level of Type I interferons and pro-inflammatory cytokines from immune cells as well as in mice treated with a STING agonist. There is significant partitioning of COMPOUND 2 into the brain after oral dosing. Once a day oral administration of COMPOUND 2 provided protection from neurodegeneration, decreased striatal tyrosine hydroxylase expression and led to a recovery in dopamine levels in MPTP treated mice. Conclusions: COMPOUND 2 is an orally administered novel first-in-class cGAMP competitive STING antagonist with high levels of brain exposure and is a promising candidate for the treatment of neuroinflammatory conditions.
Identification of immune modulating strategies to promote cartilage regeneration.
Authors: Choi Eirene , Smith Carly , O'Donnell Lauren , Collins John , Freeman Theresa 
Published: November 2024

Abstract
The immune response is a key modulator of regeneration. Apoptosis Signal-Regulating Kinase 1 (ASK1) loss can promote cartilage regeneration, thus we investigated how ASK1 loss modulates the immune response.
Two mm biopsy punches of ear tissue samples were taken from WT and ASK1 KO mice (n=3) on day 0, 4 and 7 after injury. RNA was extracted and gene expression analyzed using the NanoString nCounter Immunology Gene Panel. Functional enrichments were analyzed using Gene Set Enrichment (GSEA) and Variation (GSVA) Analysis.
GSVA showed general apoptosis and p53 pathways were significantly decreased in all KO samples, as expected. The Nanostring curated gene set across all time points and samples showed TLR, NFkB and TNF signaling down regulation. Conversely, MHC class II and cell adhesion were upregulated. GSEA indicated significant differences between cell types involved in the innate and acquired immune response. The most increased GSVA results from the Hallmark gene set was apical junction and most significant decrease was the epithelial-mesenchymal transition (EMT) and IL-6-JAK-STAT3 signaling pathway. GSEA-generated heatmaps of genes that significantly contributed to these pathways give additional insight into how ASK1 loss modulates immune signaling pathways to promote a regenerative environment.
This analysis identified signaling pathways that modulate the immune response to support a regenerative environment and insights into how to clinically modulate this process.
Understanding the role of IL-17 signaling pathway in regulating the immune response against Mtb infection.
Authors: Chauhan Kuldeep , Das Shibali , Dela Peña Noreen , Ahmed Mushtaq , Khader Shabaana 
Published: November 2024

Abstract
Tuberculosis (TB) remains a significant global health concern, with a quarter of the world's population infected. Understanding the immune response against Mycobacterium tuberculosis (Mtb) is crucial for developing effective strategies to control TB. Previous work from various groups, including our lab, has indicated that the induction of IL-17 plays a protective role during Mtb disease progression. However, the downstream cells that sense and respond to IL-17 and how they shape the induction of protective immune responses remain unclear. The current study focuses on understanding the role of IL-17RA-mediated signaling in regulating the immune response against Mtb infection. The study aims to investigate the role of IL-17 signaling in specific innate myeloid immune cell populations and its effect on TB disease progression. Using Cre-Flox based conditional knockout mice lacking IL-17RA, we explored the role of IL-17 signaling in different cellular components of myeloid immune cells, regulating disease progression and initiating the immune response. Our work elucidated the involvement of LysM-expressing cells as the primary responder to IL-17RA-mediated signaling in regulating the protective immune response against TB during the early stages of infection. By understanding the role of IL-17 signaling in the immune response against Mtb, this study aims to provide insights into potential strategies for controlling TB and improving vaccine design.
Regulation of macrophage inflammatory response by potato-derived bioactive peptide
Authors: Okeke Emeka , Udenigwe Chibuike , Ventura Esmeiry 
Published: November 2024

Abstract
The normal immune response to infection requires a well-regulated mechanism of leukocyte activation and recruitment, a process generally termed inflammation. Dysregulation of this inflammatory response is a major problem in modern medicine and is associated with several disease conditions including autoimmune diseases, cancer and even COVID-19.
Food-derived peptides with anti-inflammatory properties have gained popularity due to their availability in the daily diet and limited side effects. Previous reports have shown that the potato protein patatin has anti-inflammatory property. However, the sequence of amino acids in patatin that is critical for anti-inflammatory activity is not well established. In this work, we investigated the ability of the potato protein-derived peptide DIKTNKPVIF to down-regulate the inflammatory response of monocyte-derived macrophages (MDMs) activated with lipopolysaccharide (LPS). We found that DIKTNKPVIF inhibited the inflammatory response of MDMs to LPS as evidenced by decreased production of pro-inflammatory cytokines. Importantly, using computational and experimental screening techniques, we identified TNKPVI as the bioaccessible and biostable pharmacophore necessary for the activity of DIKTNKPVIF. Our results highlight the potential of potato-derived bioactive peptides to regulate the inflammatory response.