bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of CD4+ Tissue Resident Memory Cells in Oncogene Driven Lung Adenocarcinoma
Authors: Melese Etienne Sylvain , Franks Sarah Elizabeth , Cederberg Rachel , Seo Jung Hee , Lam Wan , Bennewith Kevin L , Lockwood William , Abraham Ninan 
Published: February 2023

Abstract
Lung cancer presents a global health risk that is responsible for over 2 million deaths worldwide every year. Tissue resident memory T cells (Trm) are critical for rapid protection to pathogens at entry points in the body, including the lung. Trm are identified as CD69+ CD103+ cells which remain in the tissue (i.e. lung), are longer-lived memory cells, and have antigen specificity. Many studies have shown clinical significance with tumour infiltrating lymphocytes (TIL) markers of CD103+ and CD69+ in solid tumour cancers. Few studies have addressed the direct or indirect mechanism of anti-tumour function of CD4+ Trm cells during tumour progression and how the tumour microenvironment impacts this. One primary role of CD4+ T cells in anti-tumour immunity is to provide aid to CD8+ effector cells. CD4+ Trm are known to have Th1 interferon responses to viral infection and Th2 type responses in allergic response leading to excess fibrosis. Little is known of the diversity of CD4+ Trm and their Type-1 or -2 phenotypes during cancer. In this study, we used a genetically engineered mouse model (GEMM) of lung adenocarcinoma (LAC), with doxycycline-inducible oncogene mutation KRASG12D. We observed a significant increase in PD-1+ CD4+ Trm with a Th2-like phenotype (CD44+ CD62L−CD103+ CD69+ PD-1+GATA3hi) in the KRASG12D tumour bearing lungs. When stimulated ex vivo with PMA/ionomycin, we found CD4+ CD69+ cells produced more IFNγ in the KRASG12DGEMM. To examine clinical relevance, we used the program KMplotter and found signatures of Trm and CD4+ Trm significantly correlated with increased survival in LAC patients. We intend to determine the functional relevance of these Th2-like CD4+ TRM cells in the tumour microenvironment.
Inhibition of JAK/STAT signaling sustain stem-like exhausted CD8+ T lymphocytes with enhanced antitumor effects
Authors: Shourian Mitra , Bourdin Benoite , Decaluwe Helene 
Published: February 2023

Abstract
T-cell exhaustion and reduced memory potential is an obstacle to successful adoptive cell therapy (ACT) of cancer. Ex-vivo expansion protocols require sustained TCR and cytokine stimulation that limit ACT efficacy and long-term persistence. We have shown that IL-2 and IL-15, JAK-STAT dependent-cytokines used in ACT expansion protocols, induce CD8+ T-cell exhaustion both in vitro and in vivo following chronic viral infection. We hypothesized that blocking JAK-STAT signaling during ex-vivo expansion protocols will limit T-cell exhaustion and sustain stemness of adoptively transferred cells. In the current study, we mimicked current ex-vivo expansion protocols using purified murine T-cells stimulated by tumor antigens in the presence of IL-2 or IL-15 and evaluated the impact of adding distinct inhibitors of the JAK-STAT pathway on expanded T cells. We observed that JAK-STAT inhibitors reduced CD8+ T-cell exhaustion and increased the number of Ly108+ TCF1+ stem-like progenitors. The reduction in T-cell exhaustion was observed by decreased expression of exhaustion markers, changes in specific transcription factors, and increased expression of effector cytokines using flow cytometry. Adoptive transfer of ex-vivo expanded T-cells to tumor-bearing mice indicated that CD8+ T-cells expanded in the presence of JAK-STAT inhibitor significantly reduced tumor size and increased mice survival after ACT. RNA-seq analysis identified a reduced exhaustion signature in JAK/STATi treated T-cells. These results suggest that targeting JAK-STAT signaling sustains potent antitumor reactivity of adoptive-transferred cells and may enhance the ex-vivo generation of stem-like progenitor CD8+ T cells for long-term survival in the host.
Lack of stem-like exhausted T cells and increased inhibitory receptor expression distinguishes diffuse large B cell lymphomas from Hodgkin lymphoma.
Authors: Vallée Alexis , Shourian Mitra , Decaluwe Helene 
Published: February 2023

Abstract
Immune checkpoint (IC) blockade has revolutionized the treatment of chemo-refractory solid tumors and has demonstrated promising results for the treatment of resistant blood cancers, including lymphoma. However, clinical response to PD1 blockade depends on the subtype of lymphoma, with durable responses observed in 70 % of Hodgkin lymphoma (HL) versus only 10 to 40% of Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL). The biological aspects that hinder the efficacy of immunotherapy in DLBCL and FL are not well-known. Since DLBCL and FL are more refractory to IC therapy than HL, we hypothesized that TILs from DLBCL and FL present a more advanced state of exhaustion than TILs from HL. We performed an immunophenotyping of TILs from 57 HL, FL or DLBCL lymphoma samples collected at diagnosis and frozen as viable cell suspension. Our data revealed that CD8 TILs from DLBCL express higher levels of ICs (PD1, Tim3 and Lag3) compared to TILs from FL and HL. Boolean analysis demonstrated that DLBCL and FL had a higher frequency of CD8T cells that co-expressed 6–7 ICs, compared to HL, suggesting more advanced exhaustion. In contrast, we observed that HL and FL exhibited significantly more stem-like exhausted cells (PD1+/Tim3−/CD38−/TCF1+) compared to DLBCL. Stem-like exhausted CD8 T cells are driven by the transcription factor TCF-1 and extensively proliferate in response to PD1 blockade. Collectively, our data indicate that TILs from DLBCL and FL express a whole array of ICs. DLBCL further lack protective stem-like CD8 T-cell subsets which correlate with poor clinical outcome. These results strengthen our understanding of the cellular defects precluding potent anti-tumor T cell functions in DLBCL and FL.
Therapeutic cancer vaccines in the Pacific Region
Authors: Sika-Paotonu Dianne 
Published: February 2023

Abstract
The growing burden of cancer globally remains of significant concern, with Pacific communities in Aotearoa/New Zealand and the Pacific Region disproportionately affected by some cancers. In addition, Pacific Peoples remain over-represented in adverse health statistics and inequitable health outcomes relating to cancer. There is potential for immunotherapy based therapeutic approaches to be directed towards helping address inequities with cancer treatment, management and outcomes for vulnerable communities, but will require careful consultation, consideration and contextualisation of the clinical setting for vulnerable communities. The purpose of this work was to ensure appropriate discussion and engagement to explore the potential for therapeutic cancer vaccines within the Pacific setting. Preliminary engagement and contextualisation efforts were undertaken as part of broader discussion and consultation activity, to explore the clinical setting and assess the potential applicability of therapeutic cancer vaccines within the clinical context in Samoa. Appropriate infrastructure and costs associated with therapeutic cancer vaccines would remain important factors given the current resource constrained setting in the Pacific. The urgent need to address late presentations and poor prognostic outcomes for cancer patients was also acknowledged. While therapeutic cancer vaccines hold potential for some cancer patients, the appropriate contextualisation, consultation and consideration will be needed to better understand and guide efforts within the Pacific setting in relation to the potential applicability of therapeutic cancer vaccines for addressing inequities.
Nasal immunization with mast cell activating small molecules protects mice against West Nile Virus infection
Authors: Johnson-Weaver Brandi T , Choi Haewoong , Chan Cliburn , Shterev Ivo , Abraham Soman , Staats Herman F 
Published: February 2023

Abstract

Objective:
Mast cell activators are a novel class of mucosal vaccine adjuvants. The polymeric compound, Compound 48/80 (C48/80), and cationic peptide, Mastoparan 7 (M7) are mast cell activators that provide adjuvant activity when administered by the nasal route. However, mast cell activating small molecules may be an adjuvant alternative that is easily synthesized with high purity compared to M7 or C48/80. The study objective is to identify small molecule mast cell activators that provide adjuvant activity in nasal West Nile virus vaccines.

Methods:
High-throughput screening assessed over 55,000 small molecules for mast cell degranulation activity. Fifteen hit compounds were down-selected to three by in vitro evaluation of immune activation activities, including cytokine production and cytotoxicity, and selection for functional diversity. These three molecules, ST101036, ST048871, and R529877, were then examined for their ability to evoke protection against West Nile virus infections in BALB/c mice when administered nasally with West Nile virus envelope domain III (EDIII) protein.

Results:
All three adjuvants evoked high levels of EDIII-specific antibody and conferred similar levels of protection, ST101036 (67%), ST048871 (73%) and R529877 (75%), which was also comparable to the protection induced by M7 (67%) but markedly higher than the levels seen with mice immunized with EDIII alone (no adjuvant 33%).

Conclusion:
Novel small molecule mast cell activators are as efficacious as previously described mast cell activating peptides and serve as potential replacements in in vivo studies.
Lipid A mimetics BECC438 and BECC470 potentiate durable and balanced immune responses using an ovalbumin murine vaccine model.
Authors: Harberts Erin M , Varisco David J , Fields James K , Izac Jerilyn R , Gardner Francesca M , Sundberg Eric J , Snyder Greg A , Ernst Robert K 
Published: February 2023

Abstract
The need for effective infectious disease vaccines has become an inescapable topic over the past year. Continued development of next-generation vaccines that provide robust protective immunity is imperative. Such vaccines will likely include an adjuvant that avoids excessive adverse reactions and allows for dose and antigen sparing. Bacterial lipid A mimetics BECC438 and BECC470 have recently emerged as lead adjuvant candidates across several experimental models of infectious disease including Yersinia pestis (plague), human papilloma virus (HPV), and influenza-A (flu). To further define BECC438 and BECC470 as immuno-adjuvants, even without antigen from an infectious pathogen, studies presented here use ovalbumin (Ova) as a model antigen in a murine prime-boost vaccine model. Higher magnitude and more balanced production of antibody isotypes IgG1 and IgG2 are observed when BECC adjuvants are compared to classic adjuvants alum and PHAD. This optimal antibody response is durable and maintained for at least 12 weeks post-vaccination. Initial experiments use C57BL6 mice and are expanded to include BALBc and CD-1 (outbred) mice. Observed immune metrics maintained similar trends across male and females, and genetic backgrounds tested. Biacore immunogenicity analysis of C57BL6 serum found an increased half-life of Ova-specific antibodies in BECC438-adjuvanted animals potentially indicative of a higher antigen binding affinity. Toxicity studies conducted in New Zealand White rabbits report that BECC438 was well tolerated with no significant reactogenicity after 50μg and 100μg intra-muscular adjuvant injection. These studies provide continued evidence supporting development of BECC adjuvants in vaccines for human use.
Presence of maternal antibody at initial respiratory syncytial virus (RSV) infection shapes innate and adaptive responses following repeat RSV exposure
Authors: Kosanovich Jessica , Eichinger Katherine , Lipp Madeline , Perkins Timothy , Empey Kerry 
Published: February 2023

Abstract
RSV is the leading cause of childhood hospitalization due to bronchiolitis and a significant risk factor for the development of allergic airway responses. Maternal vaccination has emerged as a promising strategy to protect infants against severe disease. However, the presence of maternal antibody (matAb) at primary RSV infection has been linked to development of wheeze later in life. Therefore, we sought to understand how high levels of matAb during early life RSV infection shapes innate and adaptive immune responses on repeat RSV exposure. Using a murine model of maternal vaccination, we assessed immune responses following adult RSV re-challenge of infants born to unvaccinated and RSV preF-vaccinated dams. Presence of matAb at primary RSV infection resulted in differential activation of resident lung populations at 4 days post-secondary infection (DPSI). Specifically, proliferation of IL-5+ and IL-13+ type 2 innate lymphoid cells were increased in association with elevated numbers of eosinophils in the alveolar space. At 8 DPSI, IL-4-, IL-5-, and IL-13-producing, but not IFNγ-producing, CD4+ T cells were significantly increased, indicating a dominant Th2 response in mice born to vaccinated dams. Importantly, lung inflammation and mucus production were similarly elevated in mice born to immunized and unimmunized dams, suggesting that maternal vaccination did not prevent pathology on repeat infection. Taken together, these data demonstrate that the presence of matAb at primary RSV infection differentially alters innate and adaptive immune responses on secondary RSV exposure. Understanding the mechanisms that drive differential cell activation in the presence of matAb will guide future maternal immunization strategies.
Comparison of young-versus-old cytokine expression profiles in response to TLR agonists in murine and human whole blood.
Authors: Joyner Jason A , Vora Kalpit A. , Monslow Morgan A. 
Published: February 2023

Abstract
Aging is met with multifaceted shifts in the makeup and function of immune cell populations, collectively known as “immunosenescence”, which render elderly populations more susceptible to pathogenesis of infectious disease and negatively impact responsiveness to vaccines. Highly efficacious vaccines to protect the elderly remain an unmet medical need. However, it has been demonstrated in recent years that robust vaccine responses can be generated in elderly populations through the use of adjuvants. While the positive impact of adjuvant inclusion in elderly vaccines is evident, a deeper understanding of the adjuvant-related, pathway-specific modulations necessary to overcome immunosenescence is needed. We hypothesize that by evaluating functional and phenotypic data from high-density immunoassays using aged murine and human samples we will identify mechanisms contributing to vaccine non-responsiveness in the elderly. To interrogate deficiencies in aged murine and human cytokine responses to immune pathway modulators, we utilized multiplex cytokine assays to compare young-versus-old in vitro cytokine expression of whole blood stimulated with TLR agonists. The results of these experiments will be discussed and could provide key insights for the rational use of adjuvants in vaccine development that may overcome age-related vaccine non-responsiveness and will also help bridge the gap in translatability of immune dysfunction-related findings between aged preclinical animal species and humans.
Broadly reactive human antibodies prevent and treat pneumococcal infection
Authors: Mousa Jarrod J. , Huang Jiachen , Gingerich Aaron D , Royer Fredejah , Paschall Amy V , Avci Fikri Y 
Published: February 2023

Abstract
Streptococcus pneumoniae remains a leading cause of bacterial pneumonia despite the widespread introduction of vaccines for disease prevention. While vaccines have been effective at reducing the incidence of most vaccine-included serotypes, a rise in infection due to non-vaccine serotypes, and moderate efficacy against some vaccine included serotypes have contributed to high disease incidence, particularly in the elderly. Additionally, numerous isolates of S. pneumoniae are antibiotic resistant or multi-drug resistant. Several highly conserved pneumococcal proteins that are prevalent in the majority of serotypes have been examined and tested as potential vaccines in preclinical and clinical trials. We isolated the first human monoclonal antibodies (mAbs) (PhtD3, PhtD6, PhtD7, PhtD8, PspA16) against the pneumococcal histidine triad protein (PhtD), and the pneumococcal surface protein A (PspA), two conserved and protective antigens. mAbs to PhtD target diverse epitopes spanning the entire PhtD protein, and mAb PspA16 targets the N-terminal segment of PspA. The PhtD-specific mAbs were found to bind to multiple serotypes, while PspA16 serotype breadth was limited. In addition, we examined the prophylactic and therapeutic efficacy of mAb PhtD3 in several mouse models of pneumococcal pneumonia and sepsis. mAb PhtD3 prolonged the survival of infected mice when administered 2 hours before infection or 24 hours after infection. Additionally, mAb PhtD3 was effective against pneumococcal serotypes 4 and 3, the latter of which is a leading cause of invasive pneumococcal disease. Overall, our results provide new therapeutic reagents for disease prevention, and identify regions on PhtD and PspA recognized by human B cells.
Increased disease severity of Ebola virus infection with blockade of CD47
Authors: Rao Deepashri , Carmody Aaron , O’Donnell Kyle L , Hasenkrug Kim , Marzi Andrea 
Published: February 2023

Abstract
Previous work demonstrated that blockade of the anti-phagocytic molecule, CD47 resulted in increased macrophage and dendritic cell activation, enhanced CD8+ T cell responses and significantly improved control of lymphocytic choriomeningitis virus (LCMV) infections of mice. Here, we investigated whether CD47 blockade would be effective in mice infected with Ebola virus (EBOV). Daily treatment with anti-CD47 antibody after infection resulted in increased viral replication, increased body weight loss, and decreased survival. Anti-CD47-treated mice had indications of better immune activation such as higher activation of splenic macrophages and B cells as well as increased CD8+ T cell function. However, CD47 blockade also induced a strong proinflammatory milieu of cytokines and chemokines, a hallmark feature of fatal EBOV infection. Thus, anti-CD47 treatment adversely affected disease severity in EBOV-infected mice.
A Factor H-Fc fusion protein competes with serum FH for binding to Staphylococcus aureus and boosts complement-mediated opsonization
Authors: Sage Megan A.G. , Cranmer Katelyn D. , Wycoff Keith , Sharp Julia A. 
Published: February 2023

Abstract
Staphylococcus aureus is a significant human pathogen that causes a multitude of superficial and invasive infections worldwide. As antibiotic resistance is increasing, novel therapies are in dire need. As a master of immune evasion, S. aureus produces several virulence factors to persist in the host. A primary target of staphylococcal immune evasion is the Complement system, a component of innate immunity central to controlling bacterial infections. We have previously shown that S. aureus binds Complement regulator Factor H (FH) via surface protein SdrE to inhibit Complement. To address the need for novel therapeutics and take advantage of the SdrE:FH interaction, we tested the binding and downstream effect of a fusion protein comprised of the SdrE-interacting domain of FH coupled with IgG1 Fc using a S. aureus clinical isolate known to bind FH.
S. aureus bound significantly more FH-Fc than Fc-control proteins indicating a greater affinity for SdrE compared to S. aureus Fc-binding proteins Protein A and Sbi. In the presence of normal human serum, FH-Fc competitively bound to S. aureus and reduced S. aureus recruitment of serum FH compared to Fc-control. When examining the effect of FH-Fc on complement-mediated opsonization of S. aureus, treatment with FH-Fc resulted in a slight increase in C3-fragment deposition and a significant increase in C5a generation compared to control. This may be attributed to the cumulative effect of serum FH displacement plus a boost in classical pathway activation via additional Fc presence afforded by SdrE:FH-Fc binding. Taken together, these data support FH-Fc as a potential anti-staphylococcal therapeutic. Future studies will explore how FH-Fc affects S. aureus survival when challenged with phagocytes.
Reading the writing of immunizations in mice – the quantitative assessment of secreted antibodies to evaluate the quality of immunizations
Authors: Eyer Klaus 
Published: February 2023

Abstract
Vaccination needs to prepare the immune system to rapidly secrete specific antibodies upon a future encounter with the pathogen. Assessments of this feature are often challenging to perform, as measurements using antibody titers represent only a poorly resolved average of the rapidly evolving repertoire. We recently published and described a novel, droplet-based microfluidic technology that allows the quantitative characterization of humoral immune responses with single-cell and -antibody resolution. The employed snapshot analysis in this system enables studying even rapidly evolving repertoires. Additionally, the method extracts for each secreted antibody its production rate, specificity, and affinity, offering a high-resolution view of immunization. Consequently, this system enables the investigation of the immunization-generated secreted antibody repertoire with high temporal, analytical, and spatial resolution.
This study in mice used the above method to characterize the quality of the immunization-induced immunoglobulin-G repertoire, and we correlated these measures with the recall-accessible repertoire. Here, we showed that introducing variation in the immunization schemes led to significant differences in the secreted repertoire. Additional analysis after recall allowed quantifying the accessible antibody repertoire, and due to the single-cell resolution, our data allowed us to compare these two repertoires on a phenotypical level. We showed that the relationships between the two repertoires are not trivial and strongly depend on immunization itself. In summary, the developed approach introduced a novel, quantitative, and functionally resolved alternative to study the quality of immunizations.
Disease-associated microglia are implicated in neuropsychiatric manifestations of systemic lupus erythematosus
Authors: Makinde Hadijat M , Chen Shang Yang , Mike Elise V , Putterman Chaim , Winter Deborah R , Cuda Carla M 
Published: February 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organs, including the brain. Though 50% of patients may experience neuropsychiatric symptoms (NPSLE), disease mechanisms remain largely unknown. Microglia, the resident innate immune cell of the brain, have recently been implicated in NPSLE. Microglia are heterogenous and may be associated with a homeostatic microglia (CD11clo) or a disease-associated microglia (DAM; CD11chi) state common to neurodegenerative disease and aging. Yet, few studies have examined microglia subsets in NPSLE. We showed that expression of a shared NPSLE transcriptional signature and DAM-associated genes correlates with the severity of behavioral deficits in microglia isolated from two NPSLE models prior to overt systemic disease. Further, our single-cell RNA-seq data identify homeostatic microglia and DAM states in control and NPSLE-prone mice. DAM in NPSLE are enriched for genes associated with antigen presentation but depleted for genes associated with phagocytosis, which is in contrast to DAM in neurodegenerative disease that are critical for phagocytic functions. Moreover, NPSLE CD11clo microglia upregulate genes linked to synapse pruning and phagocytosis, consistent with exacerbated synaptic pruning by microglia in models of NPSLE. We also find that restricted expression of the DAM transcriptional program in NPSLE DAM corresponds to improved behavioral outcomes in NPSLE-prone mice following treatment with fingolimod, a sphingosine-1-phosphate receptor modulator that reduces microglia activation and improves blood brain barrier integrity. These discoveries mark the first to implicate DAM as a potentially pathogenic microglia subset in NPSLE.