bluuebunny/crossref_metadata_2025_split huggingface dataset:
The inflamed phenotype in PD-L1 negative melanoma and response to checkpoint inhibitors.
Authors: Morrison Carl , Pabla Sarabjot , Nesline Mary , Gandhi Shipra , Pandey Manu , Conroy Jeffrey , Glenn Sean , Burgher Blake , Andreas Jonathan , Giamo Vincent , Papanicolau-Sengos Antonios , Ernstoff Marc C. , Galluzzi Lorenzo , Gardner Mark , He Ji 
Published: January 2023

Abstract

Background
PD-L1 positive melanoma patients, with a MEL score of 4 or 5 by immunohistochemistry (IHC), exhibited a response rate of &gt;50% to pembrolizumab in the KEYNOTE-001 trial. Across multiple tumor types, evidence supports that response to checkpoint inhibitors (CPIs) is associated with an inflamed phenotype. Currently there is very little known about predicting response to CPIs in PD-L1 negative inflamed and non-inflamed melanomas.

Methods
86 melanomas were tested using PD-L1 IHC and a custom NGS immune gene expression assay. 72 of these patients were treated with one or more CPIs. A PD-L1 MEL score of 4 or 5 was considered positive for IHC, and over expression of a majority of 43 genes related to T-cell activation and 11 genes associated with tumor infiltrating lymphocytes were considered positive for the inflamed phenotype. RECIST v1.1 was used to assess patient response

Results
8 of the 86 samples were PD-L1 IHC positive, 10 of the 86 were PD-L1 IHC negative, and all 18 samples in this group showed an inflamed phenotype. Of the 72 patients that could be evaluated for response to CPIs, 8 demonstrated an inflamed phenotype while 64 were non-inflamed.

Conclusion
A positive PD-L1 IHC MEL score of 4 or 5 fails to identify most melanoma patients with response to CPIs. The inflamed phenotype also fails. Most responders demonstrate a PD-L1 IHC negative/non-inflamed phenotype. Additional studies of the immune phenotype in melanoma are required to evaluate prediction of response to CPIs.
Secretion of IL-1β from imatinib-resistant chronic myeloid leukemia cells contributes to BCR–ABL mutation-independent imatinib resistance
Authors: Lee Wongeun , Lee Cho-Rong , Kang Jung-Ah , Yang Taewoo , Park Sung-Gyoo 
Published: January 2023

Abstract
Some cases of chronic myelogenous leukemia are resistant to tyrosine kinase inhibitors (TKIs) independently of mutation in BCR–ABL, but the detailed mechanism underlying this resistance has not yet been elucidated. In this study, we generated a TKI-resistant CML cell line, K562R, that lacks a mutation in BCR–ABL. Interleukin-1β(IL-1β) was upregulated in imatinib-resistant K562R than in the parental cell line K562S, and higher levels of IL-1β contributed to the imatinib resistance of K562R and to cell survival. In addition, IL-1β secreted by K562R cells could stimulate a bone marrow stromal cell line to produce chemokines, such as CXCL11, that lead to the migration of the CML cells into the stroma. Thus, elevated IL-1β production from TKI-resistant K562R cells may contribute to TKI resistance by increasing cell viability and promoting cell migration.
Activator of G-Protein Signaling 3 Modulates Prostate Cancer Development and Progression
Authors: Richardson Micheler , Adekoya Timothy , Smith Nikia , Mowart Tonelia A 
Published: January 2023

Abstract
Prostate cancer (PCa) is a leading cause of cancer death among men, with greater prevalence of the disease among the African American population in the US. AGS3, a receptor-independent activator of G-protein signaling has been shown to affect different cellular processes and cell cycle activity. The aim of this study is to assess the role of AGS3 on the development and progression of prostate cancer as well as to understand the molecular dynamics involved. Preliminary results indicate a differential in the level of expression of AGS3 in PCa cells with the African American cell line (MDA PCa 2b) expressing high amount of AGS3 while the Caucasian cell lines (PC3 and LNCAP) do not. Overexpression of AGS3 in PC3 augmented tumor development in nude mice xenografts whereas depletion of AGS3 in MDA PCa 2b decreased tumor size. Interestingly, a xenograft model of Lewis Lung Carcinoma (LLC) cells in AGS3 conditional knockout (AGS3−/−) mice resulted in a significant increase in tumor progression when compared with the wild-type (AGS3+/+) mice. Taken together, these results indicate that AGS3 expression modulates tumor development and progression and may play a role in PCa health disparity.
EFhd2/ Swiprosin-1 regulates the cytoskeleton of B lymphocytes and impacts germinal center reaction
Authors: Reimer Dorothea , Heyland Edmar , Wiesmann Veit , Wittenberg Thomas , Brachs Sebastian , Voehringer David , Hauser Anja , Niesner Raluca , Mielenz Dirk 
Published: January 2023

Abstract
The germinal center (GC) reaction is a decisive checkpoint for efficient humoral immunity. Most GC associated processes, e.g. cell migration and cell adhesion, are strongly dependent on cytoskeletal dynamics and B cell receptor (BCR) signaling. However, the molecular connection between downstream BCR molecules and cytoskeletal proteins is not yet fully elucidated.
The adaptor protein EFhd2/ Swiprosin-1 co-localizes with the BCR at the plasma membrane. It controls F-Actin bundling as well as Actin remodeling through Cofilin activity and is involved in spreading, lamellipodia formation and migration in non-lymphoid cells. We showed that constitutively EFhd2 deficient mice display enhanced GC responses upon challenge with the helminth Nippostrongylus brasiliensis in a B cell intrinsic manner in mixed bone marrow chimeras. Moreover, B cell specific deletion of EFhd2 leads to enhanced GC B cell numbers already in steady state. We therefore hypothesize that EFhd2 controls the GC reaction by regulating cytoskeletal processes. In vitro transwell migration assays and in vivo studies using two-photon microscopy revealed decreased directed chemotaxis but increased random chemokinesis of EFhd2−/− B cells. Moreover, activated B cells spread faster in the absence of EFhd2 on anti-BCR antibodies which correlates with accelerated Cofilin activity. Finally, also BCR capping was increased in activated EFhd2 deficient B cells.
Taken together, we suggest that EFhd2 controls Actin dynamics through Cofilin in B cells, thereby, controlling chemotaxis of B cells and BCR mediated B cell spreading. Hence, EFhd2 links proper coordination of the B cell cytoskeleton with the GC checkpoint and impacts TH2 response.
Coordinated metabolic response of dendritic cells to influenza infection
Authors: Rezinciuc Svetlana , Bezavada Lavanya , Thomas Paul G. , Smallwood Heather S 
Published: January 2023

Abstract
Infection with the influenza virus triggers an innate immune response aimed at limiting viral replication and spread. However, the molecular mechanism(s) underlying the processes of change–in innate immune cell homeostasis are not known. We show here that the influenza virus specifically alters the metabolism of dendritic cells (DCs) to enhance viral biomass production and that the metabolic response of the dendritic cells to viral infection differed from activation via TLR stimulation or infection with inactive virus. Using quantitative mass spectrometry along with pulse chase assay and metabolic flux measurements, we found that metabolic pathway changes dominated after infection, including increased glycolysis and glutaminolysis, and decreased tricarboxylic acid cycle and β-oxidation. This metabolic response to viral infection increased the expression of the c-Myc transcription factor, which indicates that influenza have the potential to induce key metabolic regulatory events. Influenza infection induces a unique metabolic signature in dendritic cells, prior to the canonical innate response to viral infection. Limiting these metabolic changes by metabolite restriction induces massive cell death in infected DCs, suggesting they play a vital role in initiating the innate immune response.
Blocking CCR10 diverts skin-homing T cells to reproductive tract for enhanced establishment of local resident memory T cells
Authors: Zhao Luming , Hu Shaomin , Davila Micha L , Xiong Na 
Published: January 2023

Abstract
Tissue-resident memory T (TRM) cells play an important role in protection against re-occurring infection. Compared with circulating memory T cells, tissue-specific TRM cells have great advantages in mounting faster and more effective responses against local infections. Female reproductive tract (FRT), which is a portal of entry for sexually transmitted infections, is an immunologically restrictive tissue that prevents progenitors of TRM cells entering in the absence of inflammation or infection. Therefore, how to increase number of TRM cells in FRT after vaccination to improve memory response against pathogens becomes an important question. In our present study, we found that a significant portion of T cells in FRT expressed the skin-homing chemokine receptor CCR10 in physiological conditions, and those CCR10+ T cells displayed surface markers typical for TRM cells. Particularly, almost all the CCR10+ CD8+ T cells expressed CXCR3, a homing marker which could help T cell migrate into FRT, suggesting the competition of skin and FRT for CD8+ T cells. After epicutaneous immunization, activated antigen-specific CCR10-knockout CD8+ T cells migrated more efficiently into FRT than CCR10-sufficient T cells. Our finding suggests that blocking CCR10 signals could divert skin-homing T cells into FRT for enhanced establishment of local resident memory T cells.
IL-17 is crucial for psoriatic inflammation, but also initiates an anti-inflammatory feedback loop via signaling into keratinocytes
Authors: Ha Hye-Lin , Wang Hongshan , Ulrich Siebenlist 
Published: January 2023

Abstract
The IL-17 cytokines make crucial contributions to chronic inflammatory skin disease and anti-IL-17 antibodies have proven to be highly efficacious in treating psoriasis. IL-17 cytokines signal via the obligatory adaptor CIKS/Act1. Previously, we have identified critical roles of CIKS-mediated signaling in imiquimod-induced psoriatic inflammation. IL-17/CIKS-mediated signaling into keratinocytes was essential for neutrophil infiltration and contributed to pathology by promoting proliferation and dampening terminal differentiation of keratinocytes. Interestingly, IL-17 signaling into keratinocytes also exerted negative feedback, delimiting continued accumulation of IL-17-producing γδ T cells in skin. We now demonstrate that the negative feedback is mediated in part via IL-19, a member of the IL-10 family of cytokines. IL-19 is strongly induced by IL-17-stimulated keratinocytes and appears to function by suppressing recruitment of IL-17-producing γδ T cells over time, thereby dampening IL-17 production. This stands in contrast to IL-17/CIKS-mediated signaling into non-keratinocytes – specifically dermal fibroblasts - which initially promoted cellular infiltration and enhanced accumulation of IL-17-producing γδ T cells in skin, comprising an early positive feed-forward mechanism. Our data show that CIKS-mediated signaling is dynamic; it is central to the development of both dermal and epidermal hallmarks of psoriasis, but also initiates mechanisms that ultimately mitigate further tissue damage. The latter mechanisms may offer additional avenues for therapeutic intervention.
Memory-phenotype CD4+ T cells spontaneously generated under steady state conditions exert innate Th1-like effector function
Authors: Kawabe Takeshi , Jankovic Dragana , Kawabe Shuko , Huang Yuefeng , Lee Ping-Hsien , Yamane Hidehiro , Zhu Jinfang , Sher Alan , Germain Ronald N , Paul William E 
Published: January 2023

Abstract
CD4+ T cells are composed of naïve, pathogen-specific memory, and pathogen-independent memory-phenotype (MP) cells. Naïve and pathogen-specific memory cells play key roles in adaptive immunity while the homeostatic mechanisms regulating the generation of MP cells and their biological functions are unclear. In this work we show that MP cells are autonomously generated from peripheral naïve cells in the absence of infectious stimulation in a TCR- and CD28-dependent manner. We further demonstrate that MP cells contain a T-bethi subpopulation that is continuously generated by environmental IL-12 and rapidly produces IFN-γ in response to IL-12 in the absence of pathogen recognition. Importantly, these cells can provide nonspecific host resistance against Toxoplasma gondii infection while enhancing the adaptive CD4+ T cell responses. Together, these findings reveal that MP cells are continuously generated from naïve precursors and possess a novel innate immune function by which they produce an early, Th1-like protective response against pathogens.
C-Myc regulation by Notch Signaling Modulates T Cell Differentiation
Authors: Song Jim Jianxun 
Published: January 2023

Abstract
Notch signaling is essential for T lineage commitment and further required during early phases of thymocyte differentiation. Active Notch signaling during early stages of T cell development inhibits other lineage potentials, such as B cell and myeloid cell (e.g., dendritic cell) potentials. However, the intracellular signaling pathways by which Notch signaling regulates T cell differentiation remain unknown. Here we show that the transcriptional factor c-Myc is controlled by Notch signaling which regulates T cell differentiation. In a well-established in vitro differentiation of T lymphocytes from stem cells, Notch signaling directly controls c-Myc expression. Overexpression of active c-Myc promotes while dominant-negative (dn) c-Myc inhibits early cell differentiation. Moreover, c-Myc expression mediated by Notch signaling modulates survivin, an inhibitor of apoptosis (IAP) protein, which is crucial for T cell development. Overexpression of active c-Myc increases while dn c-Myc reduces survivin expression, which corresponds to T cell differentiation within the in vitro differentiation system. These results identify c-Myc, together with survivin, as regulators of the differentiation of T cells from Notch signaling.
Bacterial Siderophores Hijack Neutrophil Functions
Authors: SAHA PIU , Yeoh Beng San , Olvera Rodrigo A , Xiao Xia , Awasthi Deepika , Singh Vishal , Dikshit Madhu , Wang Yanming , VIJAY-KUMAR MATAM 
Published: January 2023

Abstract
Neutrophils are primary immune cells that respond to inflammation and eliminate microbial transgression. Yet, E. coli have been reported to bloom during gut inflammation despite the heightened neutrophil activity. The survivability of E. coli in inflamed gut are not completely understood, although their production of enterobactin (Ent; a siderophore) to circumvent inflammation-induced iron scarcity may be one of the potential mechanisms. Herein, we report that Ent is not only an iron chelator, but is an immune-regulator that counter an array of neutrophil functions. We showed that Ent inhibited PMA and LPS induced generation of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) in both mouse and human neutrophils. Ent also impaired the degranulation of primary granules, inhibited phagocytosis and bactericidal activity of neutrophils, but without affecting their migration and chemotaxis. Molecular analysis revealed that Ent can chelate intracellular labile iron that are required for neutrophil oxidative responses. Other siderophores (pyoverdine, ferrichrome, deferoxamine) likewise inhibited ROS and NETs in neutrophils, thus indicating that the chelation of iron may, in part, explain their inhibitory effects. To counter iron theft by Ent, neutrophils rely on the siderophore-binding protein lipocalin 2 (Lcn2) in a ‘tug-of-war’ for iron. The inhibition of neutrophil ROS and NETs by Ent was augmented in Lcn2-deficient than WT neutrophils, but rescued by the exogenous addition of recombinant Lcn2. Taken together, our findings illustrate the novel concept that microbial siderophore’s iron scavenging property may serve as an antiradical defense system, that neutralize immune functions of neutrophils.
Understanding the determinants of CD8+ T cell immunodominance in acute HIV infection
Authors: Warren Joanna A , Xu Yinyan , Costanzo Margaret , Whale Victoria , Liu Michael P.K. , Thomas Rasmi , Tovanabutra Sodsai , Kijak Gustavo , Eller Leigh Anne , Rolland Morgane , Michael Nelson L. , Robb Merlin L. , Eller Michael A. , Goonetilleke Nilu 
Published: January 2023

Abstract
CD8+ T cells detect and clear virus-infected cells. During human immunodeficiency virus-1 (HIV-1) infection, different HIV-specific CD8+ T cell populations are expanded, each targeting a discreet epitope. These different HIV-specific CD8+ T cell populations do not arise equally, and instead establish a hierarchy (immunodominance) based on strength of T cell response to a given viral epitope. Our previous work has shown that relative immunodominance is a major determinant of the rate at which HIV can mutate to escape T cell immune pressure. The precise mechanism of how the first CD8+ T cell response to HIV is generated, and which factors determine T cell dominance is unclear. To investigate determinants of T cell immunodominance in acute HIV-1 infection (~45 days following infection), we determined all primary HIV-1 specific CD8+ T cell responses in 10 individuals in the RV217 early HIV cohort (ECHO). T cell responses were mapped against the unique infecting HIV virus/es in each individual using IFN-γ ELISpot. Across participants, the dominant T cell response mostly targeted variable regions of the HIV-1 genome. We detected a wide (4–13 epitopes) breadth of T cell response across our cohort that was independent of HLA haplotype, with all HIV-1 proteins targeted and different rates of virus escape observed. Ongoing studies are focusing on better understanding how factors, such as T cell receptor repertoire, avidity, antigen presentation and function contribute to T cell immunodominance, which in turn will inform HIV-1 vaccine design.
Control of cytotoxic T lymphocyte memory development by beta2-adrenergic receptor signaling
Authors: Estrada Leonardo Daniel , Agac Didem , Farrar David 
Published: January 2023

Abstract
Cytotoxic T lymphocytes (CTLs) play a critical role in immune responses to intracellular pathogens. CTL responses are initiated by T cell receptor signaling, and they can be modulated by secreted factors, such as cytokines and other extracellular signals. Previous research from our lab demonstrated that the acute effector functions of CTLs are regulated by the neurotransmitter norepinephrine (NE) via beta2-adrenergic receptor (ADRB2) signaling in vitro. We now demonstrate that ADRB2 signaling intrinsically modulates in vivo memory development in response to viral infection using an adoptive transfer model. Expansion of ADRB2-deficient CTLs is unaffected during the initial priming phase in response to the model pathogen, vesicular stomatitis virus. However, ADRB2-deficient CTLs contract rapidly and do not yield any detectable pools of memory cells when compared to wild-type counterparts. Transcriptome analysis revealed a variety of differentially expressed genes, both expressed in resting naïve cells as well as in cells obtained during the primary expansion phase of infection. Among them, we found that the expression of the high affinity IL-2Ra (CD25) was reduced during the activation phase in ADRB2-deficient cells, which was confirmed at the protein level by flow cytometry. While IL-2 responsiveness is a key determinant in programming memory cell development, treatment with IL-2/anti-IL-2 complexes during early phases of infection failed to rescue memory formation of ADRB2-deficient cells, despite a restoration of CD25 expression on day 5 post-infection. Future experiments will dissect the role of ADRB2 signaling during CTL development on the capacity to form memory upon antigen exposure.
Negative regulation of IFNAR1/2 Signaling by USP18 is required for immunity to Listeria monocytogenes
Authors: Flores Ricardo , Mavinkurve Vikram , Muthukumaran Geetha , Cabasal Marian , Nguyen Tammy , Rajan Robin , La-Beck Irene , Paterson Yvonne , Wood Laurence M 
Published: January 2023

Abstract
Listeria monocytogenes (LM) is a bacterial pathogen linked to an increasing number of infections in countries with aging populations and a high mortality rate in immunocompromised patients. The immune response to LM is well-studied due to its proficient induction of T cell responses, a key attribute leading to its development as a vaccine platform. Thus, mechanisms regulating immunity to LM are of significant interest. In this study, we report that ubiqutin-specific protease 18 (USP18), a key regulator of Type I IFN signaling, is induced during LM infection and is necessary for a functional immune response to the pathogen. Our studies demonstrate that USP18 deficiency results in severe susceptibility to primary LM infection and an inability to develop functional adaptive immunity to LM. Increased susceptibility to LM infection in USP18−/− mice was associated with impaired inflammatory cytokine responses, reduced dendritic cell (DC) maturation, blunted splenic T cell function, and elevated immunosuppression. This defective immune response to LM in mice lacking USP18 is due in large part to unregulated Type I IFN signaling. Inhibition of signaling through IFNAR1/2 resulted in a dramatic reversal of LM susceptibility in USP18−/− mice as evidenced by improved LM infection control, DC maturation, T cell function, and induction of protective immunity. Therefore, we find that USP18 deficiency results in an IFNAR1-dependent susceptiblity to LM infection and impairment of protective memory responses; a finding with broad application to disease prevention and vaccine development.
PD-1 signals instruct a critical metabolic switch for maintenance of T cell memory
Authors: Yuzefpolskiy Yevgeniy , Baumann Florian M , Penny Laura A , Kalia Vandana , Sarkar Surojit 
Published: January 2023

Abstract
PD-1 is highly expressed on CD8 T cells during activation, both in acute and chronic viral infections. Inhibitory signaling in cytotoxic T cells through the PD-1 axis is well characterized during chronic infections and has led to the development of clinical checkpoint blockade therapies that restore function to otherwise exhausted CD8 T cells. However, the functional significance of transient PD-1 expression on T cells early after activation during acute infections remains yet to be characterized. It is paradoxical that expression of PD-1 (an inhibitory receptor) during activation temporally coincides with rapid proliferation and production of copious amounts of signature effector cytokines (IFN-γ and TNF-α). Our studies using PD-1−/−antigen-specific CD8 T cells revealed an unexpected lack of an inhibitory role for PD-1 early during priming - PD-1−/−T cells exhibited similar proliferation, accumulation, cytotoxicity and polyfunctionality compared to WT T cells. Surprisingly, PD-1−/−T cells underwent precipitous contraction, leading to near ablation of the memory pool. Mechanistically, PD-1−/−memory Tcells showed a severe defect in antigen-independent homeostatic proliferation in vivo, despite identical expression of common gamma-chain cytokine receptors as WT T cells. Notably, PD-1−/−memory T cells failed to optimally switch the critical utilization of glucose to fatty acid as an energy source, which impaired their homeostatic maintenance and resulted in attrition. These findings show a previously unrecognized role of PD-1 signaling in programming a metabolic switch that is critical for the maintenance of memory CD8 T cells and could make it a novel target for manipulating vaccine-induced memory T cell longevity.