bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ibrutinib has a novel immunomodulatory effect by enhancing DC maturation both in vivo and in a model of inflammation
Authors: Saljoughian Noushin , Varikuti Sanjay , Halsey Gregory , Oghumu Steve , Satoskar Abhay 
Published: January 2023

Abstract
Myeloid derived suppressor cells (MDSCs) can inhibit T cell activation by altering the characteristics and activation of dendritic cells (DCs). We had previously reported that Ibrutinib enhances the expression of co-stimulatory molecules on DCs and promotes DC-mediated T cell activation. In the present study we further determined the mechanisms of DC immunomodulation by Ibrutinib. We evaluated the effect of Ibrutinib on (i) DC maturation and migration from the injection site to draining lymph nodes, (ii) T cell proliferation in vivo, and (iii) monocyte maturation to DCs using a mouse inflammation model. DCs were generated from mouse bone marrow-derived cells in the presence of vehicle or 10μM lbrutinib. CFES-labelled DCs were injected subcutaneously into the footpads of naive mice, and their migration to the regional lymph nodes and maturation profile was analyzed by flow cytometry. To evaluate T cell priming, CFSE-labelled OVA-specific T cells isolated from OT-II mice were injected into the tail vein of syngeneic mice that were prior injected with mature DCs loaded with OVA peptide. After four days, T cell proliferation was evaluated by CFSE dilution. In the inflammation model, C57BL6 mice were treated with vehicle or 6mg/kg/day Ibrutinib orally for a week. A sub-lethal dose of LPS was injected in the dorsal skin and the frequency of inflammatory monocytes and mature DCs was determined. We found that Ibrutinib significantly improves DC maturation and migration, inducing T cell activation and proliferation in vivo. In addition, Ibrutinib enhances monocyte maturation to DCs in the skin. The results suggest a novel effect of Ibrutinib, which may have therapeutic use for cancers characterized by a high MDSC infiltration.
The DNA methyltransferase inhibitor, Guadecitabine, shifts myeloid derived suppressor cell phenotype from immune-suppressive toward immune-stimulatory.
Authors: Luker Andrea , Graham Laura , Tolete Christina , Conrad Daniel , Bear Harry 
Published: January 2023

Abstract
Immune-evasion is a difficult obstacle to overcome in cancer therapy. Through the epigenetic modifications of DNA methylation and the recruitment of immunoregulatory myeloid-derived suppressor cells (MDSCs), tumors are able to dampen the body’s anti-tumor response. Here we show that the DNA methyltransferase inhibitor, Guadecitabine, is an effective tool for altering both tumor and MDSC phenotype. Treatment of 4T1 murine mammary carcinoma cells in vitro with Guadecitabine caused a significant increase in MHC I. In MDSCs, Guadecitabine caused an increased expression of MHC II and CD86, and enhanced antigen uptake. Additionally, Guadecitabine-treated MDSCs had a reduced capacity to block T cell proliferation, at least in part due to diminished nitric oxide production. In vivo, we established 4T1 flank carcinomas for 10 days prior to administering Guadecitabine. The resulting tumor size was markedly reduced and the characteristic splenomegaly from MDSC accumulation was largely reversed. Importantly, Guadecitabine did not affect resident lymphocyte populations in the spleen or infiltration to the tumor. Overall, these results suggest that Guadecitabine may be an effective therapy to boost the patient’s own immune response against cancer.
Tristetraprolin regulates CD8 T cell functions and antitumor immunity through targeting IL-12 family cytokines
Authors: Liu Jianguo , Wang Qinghong , Ning Huan , Hou Rong 
Published: January 2023

Abstract
IFN-γ-producing CD8+T cells (CTLs) are essential for host defense against viral infection and cancer. The mechanisms that regulate the development and function of CTLs still remain largely elusive. Tristetraprolin (TTP) is an RNA-binding protein that promotes decay of the mRNAs encoding cytokines produced in macrophages. We recently found that CD8T cells of TTP deficient mice showed effector phenotype and produced more IFN-γ than CD8 T cells of WT mice. When isolated naïve CD8 T cells were activated in vitro, however, IFN-γ production by WT and Zfp36−/−CD8 T cells was comparable. We found that the levels of IL-27 and IL-12 in serum were increased in Zfp36−/− mice compared to WT mice both at the resting state and after LPS challenge. Macrophages deficient of TTP produced more IL-27 and IL-12. Furthermore, we discovered that TTP inhibited IL-27 by promoting p28 mRNA degradation whereas suppressed IL-12 by affecting NF-kB signaling. Deletion of IL-27 receptor WSX-1 in Zfp36−/−mice (WSX-1/TTP double KO) led to a reduction in CTLs. In a murine mammary gland tumor model, tumor growth was suppressed in Zfp36−/−mice, and this suppression was almost completely abolished in the WSX-1/TTPdouble KO mice and after depleting CD8 T cells. Our study unveils a novel regulatory pathway for CTL function and antitumor immunity regulation mediated by TTP.
The impact of TCR affinity on T cell differentiation and dysfunction in tumors
Authors: Shakiba Mojdeh , Philip Mary , Camara Steven , Socci Nicholas D. , Schietinger Andrea 
Published: January 2023

Abstract
Although tumor-specific CD8 T cells are found in human tumors, cancers progress, indicating that these T cells are dysfunctional; yet the regulatory mechanisms underlying tumor-specific T cell dysfunction remain poorly defined. T cell-mediated immune responses are triggered by T cell receptor (TCR) binding to peptide-major histocompatibility complex (pMHC). In acute infections, affinity of TCR:pMHC interaction is a critical determinant of T cell expansion and effector function. However, little is known about how tumor antigen affinity impacts T cell differentiation and dysfunction in progressing tumors. To investigate the functional and molecular programs determined by affinity, we generated an in vivo tumor model expressing altered peptide ligands (APL) derived from SV40 large T antigen epitope I (TAG) and recognized by TAG-specific transgenic CD8 T cells (TCRTAG) with varying functional avidity. While affinity did not impact T cell activation and differentiation in tumor draining lymph nodes, it drove distinct functional and molecular programs at the tumor site. Interestingly, key transcription factors and effector molecules were regulated by signal strength, preserving a cell-intrinsic functional program in T cells with low-affinity interactions. In contrast, certain hallmarks of T cell dysfunction, including the expression of inhibitory receptors (e.g. PD1 and LAG3), were affinity-independent, revealing that even very weak TCR ligations can induce a typical exhaustion phenotype. Ongoing studies will define the transcriptional and epigenetic programs underlying the distinct dysfunctional T cell states in tumors driven by TCR signal strength.
Regulation of Chitinase-3-like-1 in T cell enhances anti-tumoral T cell responses to suppress lung metastasis
Authors: Kim Do-Hyun , Lim Sangho , Lee Hong-Gyun , Lee Chun Geun , Elias Jack A. , Choi Je-Min 
Published: January 2023

Abstract
Chitinase-3-like-1 (Chi3l1) is known to play a significant role in the pathogenesis of Type 2 inflammation and cancer. However, the function of Chi3l1 in T cell and its clinical implications are largely unknown. Here we showed that Chi3l1 expression was increased in Th2 cells while it decreased in Th1 cells by time dependent manner. In addition, Chi3l1-deficient T cells were hyper-responsive to TcR stimulation and were prone to differentiating into Th1 cells, and retroviral transduction of Chi3l1 rescue increased IFNγ expression in Chi3l1-deficient Th1 cells. Chi3l1-deficient Th1 cells showed increased expression of anti-tumor immunity genes and decreased Th1 negative regulators. Deletion of Chi3l1 in T cells in mice showed reduced melanoma lung metastasis with increased IFNγ and TNFα-producing T cells in the lung. Furthermore, knockdown of Chi3l1 expression in the lung using peptide-siRNA complex efficiently inhibited lung metastasis with enhanced Th1 and CTL infiltration and functions. Collectively, this study demonstrates Chi3l1 is a novel regulator of Th1 and CTL which could be a therapeutic target to enhance anti-tumor immunity.
IL-37 mediates the anti-tumor activity in hepatocellular carcinoma via T cell activation and angiogenesis suppression
Authors: Mei Yu , Teng Wantian , Teo Huey Yee , Liu Haiyan 
Published: January 2023

Abstract
IL-37 has been shown to play an immunosuppressive role against inflammatory and autoimmune diseases. However, the role of IL-37 in tumor development is still controversial. Recent studies demonstrated that IL-37 could recruit NK cells, stimulate CD4+ T cell activation, as well as inhibit tumor angiogenesis to suppress tumor progression in different tumor models. Other studies suggested that IL-37 could affect DC function to suppress adaptive immune response. In the current study, we found that IL-37 could directly inhibit hepatocellular carcinoma (HCC) cell expansion and promote its apoptosis. The in vivo results showed that IL-37 could inhibit HCC development through enhancing the T cell cytokine production and killing capacity in murine orthotopic HCC model and DEN-induced HCC model. This anti-tumor effect was fully abrogated in NOD-SCID mice. Furthermore, we found that IL-37 could also inhibit tumor angiogenesis in peritumoral areas. The in vitro study showed that recombinant IL-37 protein could directly promote the migration, tube formation and IL-1R8, VEGF, MMP2 expression in HUVEC cells. However, the supernatant from IL-37 expressing HCC cells showed an inhibition on the HUVEC cell migration and tube formation, suggesting its secondary role on angiogenesis through tumor cells could be dominant in the tumor microenvironment. Overall, these results showed that IL-37 could suppress HCC development through T cell activation and angiogenesis suppression.
Glucocorticoid receptor signaling during prolonged psychological stress compromises the ability of invariant NKT cells to participate in antitumor immune surveillance
Authors: Rudak Patrick T. , Choi Joshua , Haeryfar S.M. Mansour 
Published: January 2023

Abstract
The nervous system serves critical roles in the regulation of immune responses. Consequently, the neuroimmune functional interface can be disrupted by psychological stress, potentially impeding our ability to combat malignancies. Invariant natural killer T (iNKT) cells are innate-like T cells that, upon activation by glycolipid antigens and/or select environmental cues such as inflammatory cytokines, participate in antitumor immune responses. However, how mediators of stress may impact iNKT cell functions in this context remains unexplored. We subjected BALB/c and/or C57BL/6 mice to prolonged psychological stress, in a well-established model of physical restraint, before administering α-GalCer (a glycolipid agonist of iNKT cells) or a combination of IL-12 and IL-18. We report that stress abrogates IFN-γ production by activated iNKT cells in vivo, an effect that is reversible by blockade of glucocorticoid receptors. Accordingly, α-GalCer-stimulated iNKT cells in stressed mice failed to protect against pulmonary metastasis of B16-F10 melanoma. We also observed that otherwise α-GalCer-transactivated NK cells from stressed mice had a diminished capacity to lyse YAC-1 lymphoma cells. Finally, the suppressive effect of stress on iNKT cells was not due to their apoptotic death. In fact, unlike conventional T cells, iNKT cells were resistant to glucocorticoid-induced apoptosis. Taken together, our findings define a novel mechanism underlying stress-induced immunosuppression, which involves innate-like but not conventional T lymphocytes.
Enhancing the immunotherapeutic Trastuzumab for selective activity in the low pH tumor microenvironment
Authors: Nguyen Annalee W. , Liu Yutong , Maynard Jennifer 
Published: January 2023

Abstract
Highly selective killing of tumor cells is a key requirement for a successful and tolerable intervention in cancer treatment. While immunotherapies have been revolutionary in reducing the systemic impacts of chemotherapy, dramatic and sometimes life-threatening side effects can occur when selectivity is not stringent enough. For example, the popular HER2+ breast cancer therapeutic Trastuzumab has well-documented cardiotoxic effects due to expression of HER2 on cardiomyocytes. To enhance selectivity of immunotherapeutics for tumor cells, we can take advantage of the unique tumor microenvironment and its low pH relative to healthy tissues to bias the activity of antibodies toward tumor tissues. We have engineered antibodies for enhanced binding and efficacy at low pH, which may alleviate the requirement for binding an antigen that is only present on cancer cells while simultaneously reducing side effects due to binding non-tumor cells. Trastuzumab CDRs were mutagenized and screened for binding of HER2 antigen at a tumor pH of 6.5 and reduced binding at the normal tissue pH of 7.4. In a more generalizeable approach, the Fc region of Trastuzumab was also mutagenized and screened for similar pH dependent binding to FcγrIIIA, the interaction responsible for recruitment of key anti-tumor natural killer cells. All library screening took place on the surface of CHO cells, ensuring selection of clones that express well and contain the glycosylation necessary for Fc structure and function. Improved Trastuzumab variants identified through this work have the potential to dramatically improve this popular breast cancer therapy by reducing the cardiotoxic side effects, making the therapy more tolerable and available to more patients.
Agonist Redirected Checkpoint (ARC), SIRPα-Fc-CD40L, for Cancer Immunotherapy
Authors: Fromm George , de Silva Suresh , Patel Arpita , Johannes Kellsey , Hornblower Josiah , Schreiber Taylor H. 
Published: January 2023

Abstract
Combination immunotherapy with bispecific abs, linked scFv’s or T cell engagers have not shown that both checkpoint blockade and TNF receptor activation can be achieved with a single molecule, likely due to a loss of target avidity. Fusion proteins incorporating the extracellular domain of type I membrane proteins (eg. Enbrel) or type II membrane proteins (eg. SIRPα-Fc), linked via an antibody Fc domain, are both functional despite the ECDs being in opposite orientation. We report the generation of a two-sided fusion protein (ARC) incorporating the ECD of SIRPα (CD172a) and the ECD of CD40L, adjoined by a central Fc domain.
The SIRPα end of the ARC binds CD47 at 3.59 nM affinity, but does not cause hemolysis, compared to CD47 mAbs. The CD40L end binds CD40 at 756 pM affinity and binds CD40 on primary macrophages. The SIRPα-Fc-CD40L ARC stimulates NFκB-functional activity (independent of Fc receptor cross-linking) and IL2 and TNFα secretion in an ex vivo super-antigen (SEB) assay. Furthermore, live cell imaging shows that SIRPα-Fc-CD40L enhanced phagocytosis of tumor cells by primary macrophages. Finally, the therapeutic activity of SIRPα-Fc-CD40L in established murine MC38 and CT26 tumors was superior to either CD47 blocking antibody, CD40 agonist antibody or their combination. Finally, treatment of cynomolgus macaques with SIRPα-Fc-CD40L was safe, and no evidence of hemolysis or thrombocytopenia was observed. These data demonstrate feasibility of a novel chimeric fusion protein platform, providing checkpoint blockade and TNF superfamily costimulation in a single molecule, which may uniquely poise macrophages in the TME for activation and cross-presentation of tumor antigens following enhanced tumor cell phagocytosis.
Detection of Immune Cell Markers and Metabolic Profiles in Saliva and Oral Brush Samples from Oropharyngeal Cancer Patients
Authors: Parker Katherine H. 
Published: January 2023

Abstract

Aims
HPV is a predominant cause of oropharyngeal cancers (OPC) in the US. HPV-related OPC incidence is more common in, and rapidly increasing among males. Immunity at the oral cavity in the context of OPC is still unknown. To better understand the oral immune environment in OPC, we assessed immune-cell markers/populations and metabolic profiles in oral specimens from OPC patients and controls.

Method
Fifty newly diagnosed OPC patients, and fifty age-matched controls were recruited at the Moffitt Cancer Center. Flow cytometry was performed on cells in saliva, and those collected with Orcellex® Brushes. Innate-immune and lymphocytic markers were examined within CD45+ cells. Metabolic profiles of saliva supernatants were assessed using ultrahigh performance liquid chromatography-tandem mass spectroscopy at Metabolon.

Results
Percentage of CD1a+, CD14+, CD3+, CD56+, and CD163+ cells within the leukocyte gate were reduced in saliva in cases compared to controls (two-tailed Mann-Whitney test, p &lt; 0.05). Lipid oxidation was elevated in OPC cases, possibly stemming from reduced glycolysis. Moreover, a significant increase in 3-hydroxybutyrylcarnitine, aconitate, and 2-methylcitrate was observed (Welch’s two-sample t-test, p &lt;0.05), as well as a trend in reduction of glucose, pyruvate, lactate, and glycate in cases. Additional proteomic analyses of saliva are under way to better understand protein profiles in OPC. Our findings suggest that immune cell populations are reduced in OPC cases, which may lead to immune suppression. Furthermore, the increase in lipid oxidation is suggestive of increased oxidative stress. Future studies are needed to confirm findings and delineate the role of these markers in cancer development.
Activation of the CD137 Pathway in T cells by a CD137 × 5T4 bispecific ADAPTIR Molecule Requires Co-engagement of CD137 and 5T4
Authors: Blahnik-Fagan Gabriele R. , Bader Robert , Bannink Jeannette , Mitchell Danielle , Misher Lynda , McMahan Cathy , Bienvenue David , Fritzell Sara , Säll Anna , von Schantz Laura , Ellmark Peter , Nelson Michelle , Hernandez-Hoyos Gabriela 
Published: January 2023

Abstract
CD137 (4-1BB) is a key costimulatory immune receptor (member of the TNFR-superfamily) that is expressed primarily on activated CD8+ T and NK cells. Stimulation of CD137 leads to enhanced proliferation, increased survival, intensified cytolytic activity of T cells and induced IFN-γ production. CD137 monoclonal antibody therapies have shown promising anti-tumor effects in the clinic, but systemic immune stimulation have induced dose-limiting hepatic toxicities. A novel bispecific antibody (ALG.APV-527) was developed based on ADAPTIR™ technology to direct the activation of T cells and NK cells to the tumor area, thereby minimizing systemic toxicity. ALG.APV-527 contains binding domains to the costimulatory molecule CD137 and the tumor-associated antigen 5T4. 5T4 is a tumor antigen expressed on a variety of solid tumor types. ALG.APV-527 was generated with binding domains from the Alligator-Gold® human scFv library, and has been optimized for binding and function. ALG.APV-527 increased CD8+ T-cell activation, as measured by IFN-γ production, but only in the presence of 5T4-expressing cells. Additionally, the CD137 ×5T4 bispecific antibody enhanced proliferation of primary T cells and increased potency in an NF-κB reporter assay. Of importance, the binding affinity and function of ALG.APV-527 retained a low Ec50 (nM range) regardless of the level of 5T4 expression on target cells. In conclusion, we have developed a novel ADAPTIR™ bispecific molecule that, based on preclinical data, has potential as a promising therapeutic for the treatment of a variety of 5T4-expressing solid tumors.
Combination of TLR8 and TLR4 agonists reduces the degrading effects of nicotine on DC-NK mediated effector T cells generation
Authors: Nouri-Shirazi Mahyar A. , Tamjidi Saba , Nourishirazi Erika 
Published: January 2023

Abstract
It is recognized that cigarette smoke dampens the immune system and increases the risk of vaccine-preventable diseases. Studies suggest that combining more than one TLR agonists enhances the magnitude of immune responses to vaccination. We reported that TLR agonists acted in synergy and promoted human DC maturation, DC-NK crosstalk and ultimately naïve T cells polarization into effector Th1 and Tc1 cells.
In this study, we studied whether the combination of TLR agonists could diminish the degrading effects of nicotine, the immunosuppressive component of cigarette smoke, on human DC-NK mediated effector T cell generation.
We found that none of TLR agonists, single and combined, were able to diminish completely the adverse effects of nicotine on DCs. However, TLR3, TLR4, and TLR8 agonists acted as the most effective adjuvants to increase the expression levels of antigen-presenting, co-stimulatory molecules and production of cytokines by nicotine-exposed DCs (nicDCs). When combined, TLR3+8 and TLR4+8 synergistically optimized nicDC maturation and IFN-γ secretion from nicotine-exposed NK (nicNK) during co-cultures. Interestingly, in contrast to DC-NK-T, co-cultures of nicDC-nicNK-T treated with TLR3+8 or TLR4+8 agonists produced similar frequency of effector memory CFSE-CCR7− Th1 and Tc1 cells. However, the effector cells from TLR4+8 followed by TLR3+8 treated nicDC-nicNK-T co-cultures produced significantly more IFN-γ when compared with aluminum salt treated co-culture.
Our data suggest that the addition of appropriate TLR agonists to vaccine formulation could potentially augment the vaccination outcome in smokers.
Efficacy of a Prototype Live-vectored Multi-antigen African Swine Fever Virus Vaccine
Authors: Mwangi Waithaka , Lokhandwala Shehnaz , Popescu Luca , Sangewar Neha , Elijah Catherine , Petrovan Vlad , Stoian Ana , Olcha Mathew , Bray Jocelyn , Waghela Surya , Kerrigan Maureen , Rowland Raymond R. R. 
Published: January 2023

Abstract
Subunit vaccine development against some complex pathogens require inclusion of multiple targets to optimize efficacy and or broaden protection against diverse strains. To hasten vaccine development, it is rational to evaluate efficacy of a prototype vaccine in the actual outbred host that require protection. African Swine Fever Virus (ASFV) is a complex high-consequence Transboundary Animal Disease pathogen for which there is no vaccine or treatment available. Current evidence shows that protection against the ASFV can be stimulated with a vaccine since pigs that recover from infection with less virulent isolates are protected against closely related virulent isolates. In addition, there is evidence that ASFV-specific cytotoxic T lymphocytes (CTLs) are required for viral clearance. We have tested protective efficacy of several adenovirus-vectored prototype formulations containing multiple rationally selected ASFV antigens. Homologous prime-boost immunization of commercial pigs with one of the experimental vaccine induced significant and unprecedented antigen-specific CTL responses that were detectable in peripheral blood mononuclear cells (PBMCs). Significant IFN-gamma-secreting cells were also detected in PBMCs post-priming and the memory was recalled upon boost. In addition, the immunogen primed antibody responses that were recalled upon boost. More importantly, the prototype vaccine conferred protection in 5/9 of vaccinees following intranasal challenge with the ASFV Georgia 2007/1 isolate. Notably, these survivors were healthy with low clinical scores. In comparison, only 2/5 of the negative controls were alive 17 days post-challenge and they had high clinical scores that necessitated termination.