bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natriuretic peptide receptor A knock out restricts tumorigenesis through ablation of myeloid derived suppressor cells expansion (66.3)
Authors: Nelson Allison , Mohapatra Subhra , Mohapatra Shyam , Nagaraj Srinivas 
Published: January 2023

Abstract
Recent data from our group and a number of others have demonstrated that expansion and activation of Myeloid Derived Suppressor Cells(MDSC) play a pivotal role in tumorigenesis. The receptor for atrial natriuretic peptide, natriuretic peptide receptor A (NPRA) has been implicated in cancers. We have shown that NPRA expression and signaling is important for tumor growth. We hypothesize a novel link between NPRA expression, altered differentiation of myeloid cells and tumor formation. MDSC population consists of two major subsets of Ly6G+ granulocytic and Ly6C+ monocytic cells. Almost all tumor models demonstrated a preferential expansion of granulocytic subset of MDSC. MDSC isolated from tumor bearing mice expressed high levels of NPRA. Next we hypothesized that NPRA knock out would result in restricted tumor growth. Using NPRA deficient mice, we report that these mice have altered differentiation of myeloid cells. As a consequence tumor cells injected subcutaneously to NPRA KO mice failed to grow. We investigated the nature of cells responsible for tumorigenesis and proved that ablation of a subset of MDSC cells restricts tumor formation. This work may indicate key roles for NPRA in myeloid cell differentiation and cancer formation.
Macrophage polarization in the tumor following radiation therapy is mediated by NFκB p50 (66.30)
Authors: Gough Michael , Nguyen Cynthia , Cottam Benjamin , Savage Talicia , Crittenden Marka 
Published: January 2023

Abstract
By causing the death of cancer cells, radiation therapy has been proposed to provide both tumor antigen and endogenous immune adjuvants to initiate de novo tumor-specific immune responses. However, our experiments have shown that following radiation therapy of tumors in mice there is a rapid influx of tumor macrophages that polarize towards immune suppression. In this study we investigate the mechanisms by which newly recruited macrophages are polarized following exposure to irradiated cancer cells. Macrophage exposure to irradiated cancer cells causes a switch from TNFα to IL-10 secretion following LPS stimulation. Using luciferase reporter assays we identify that this is a transcriptional switch consistent with the action of NFκB p50 homodimers. Using macrophages from knockout mice we confirm that the immune suppressive polarization of macrophages following exposure to irradiated cancer cells requires NFκB p50. To identify the source of the upstream signal causing macrophage polarization, we determined that combined blockade of the TGFβ receptor and the Mer receptor for Gas6 bound to exposed phosphatidylserine was able to restore TNFα secretion on LPS stimulation. We propose that wound repair following radiation therapy limits control of residual disease by increasing immune suppression in the tumor. Directing the polarization of newly recruited tumor macrophages following radiation therapy represents a strategy to enhance adaptive immune control of residual cancer cells.
A molecular mechanism of tumor mediated suppression of dendritic cell differentiation (66.41)
Authors: Farren Matthew , Carlson Louise , Lee Kelvin 
Published: January 2023

Abstract
Cancer-induced immunosuppression contributes to tumor outgrowth and occurs, in part, via tumor-mediated dysregulation of DC-differentiation, resulting in immunosuppressive immature myeloid cells and fewer dendritic cells (DCs). Tumors impair DC-differentiation via factors that hyperactivate STAT3 in DC progenitors, though the mechanisms by which this inhibits DC-differentiation are poorly defined. PKCβII is essential in DC-differentiation. Here, we hypothesize that tumor driven STAT3 activity inhibits DC-differentiation by downregulating PKCβII expression. In most breast cancer patients tested, circulating myeloid cells had significantly decreased PKCβII expression (p&lt;0.03). Myeloid cells from tumor bearing mice also had decreased PKCβII expression. In vitro, culture in tumor conditioned media (TCM) decreased PKCβII protein levels (~50%), significantly decreased PKCβII mRNA levels (p&lt;0.01) and decreased phorbol ester driven DC-differentiation (p&lt;0.01) in a human model (KG1). TCM also significantly reduced PKCβ promoter activity (p&lt;0.01). TCM drove rapid STAT3 activation and STAT3 binding to the PKCβ promoter, suggesting that STAT3 downregulates PKCβII promoter activity. Clones stably expressing a constitutive active STAT3 construct had significantly decreased PKCβII expression (p&lt;0.05), an effect blocked by STAT3 inhibitors. This argues that tumor-driven STAT3 hyperactivation downregulates PKCβII expression in DC progenitor cells, inhibiting DC-differentiation.
Dual TCR/common gamma chain cytokine signaling regulates OX40 expression and synergizes with OX40 ligation to augment anti-tumor immunity (66.42)
Authors: Redmond William , Triplett Todd , Floyd Kevin , Weinberg Andrew 
Published: January 2023

Abstract
The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of the OX40 receptor can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, several agonist OX40-specific agents are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, whether additional downstream signals are needed to regulate OX40 remains unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2R-directed cytokine therapy synergized to augment anti-tumor immunity by reviving the anti-tumor efficacy of anergic tumor-reactive CD8 T cells in vivo. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 receptor expression and demonstrate a novel means of augmenting cancer immunotherapy by restoring the function of tumor-specific T cells.
CpG ODN-induced alteration of MDSC during immunotherapy of advanced renal cell carcinoma (66.44)
Authors: James Britnie , Kucaba Tamara , Norian Lyse , Griffith Thomas 
Published: January 2023

Abstract
Myeloid derived suppressor cells (MDSC) are immature, activated myeloid cells that can suppress T cell function via multiple mechanisms and dampen antitumor immunity. Using an orthotopic model of advanced renal cell carcinoma (RCC), in which lung metastases arise spontaneously from the primary renal tumors, we have been evaluating the efficacy of an antitumor therapy consisting of a recombinant adenovirus encoding TRAIL (Ad-TRAIL) combined with CpG ODN. In the present study, we examined the extent to which MDSC suppress antitumor immunity after Ad-TRAIL/CpG ODN therapy. We found a high frequency of CD11b+ CD11- Gr-1+ cells at the primary tumor site; these MDSC suppress T cell proliferation in vitro. Ad-TRAIL/CpG ODN therapy given at the primary tumor site decreased MDSC numbers at the primary tumor site, metastatic lung, and spleen, and also induced systemic CD8 T cell-mediated antitumor immunity and clearance of primary RCC tumors and lung metastases. Subsequent analysis revealed that CpG ODN alone is able to modulate MDSC frequency, phenotype, and function at the primary tumor site, metastatic lung, and spleen. Current studies are investigating the mechanism by which CpG ODN, either alone or in combination with Ad-TRAIL, modulates the frequency and function of MDSC. We are also investigating the ability of Ad-TRAIL/CpG ODN, administered in combination with MDSC-depleting anti-Gr-1 mAb, to further reduce tumor progression and MDSC numbers.
RNA aptamer against the IL-10 receptor block IL-10 function in vitro and in vivo (66.46)
Authors: Berezhnoy Alexey , Stewart Charles , Giagrande Paloma , McNamara James , Trinchieri Giorgio , Gilboa Eli 
Published: January 2023

Abstract
IL-10 is a key mediator of immune suppression in malignancies and during chronic infections. In mice, the inability of the immune system to clear viral infections and tumor growth can be reversed by antibody-mediated blockade of IL-10 action. Given the limited availability of clinical grade anti-IL-10 or anti-10 receptor antibodies, we have developed an RNA-based, nuclease-resistant, aptamer that binds to the murine IL-10 receptor (IL-10R). The IL-10R aptamer was isolated using a modified SELEX protocol starting from a random 1014 library of 80nt long oligonucleotides containing pyrimidines with 2’fluoro-modified bases. After 5 rounds of selection followed by high-throughput Solexa sequencing we generated several IL10 receptor binding aptamers with Kd ranging from 12 to 35 nM. The best candidate was further truncated to 48 nt - size suitable for chemical synthesis - which also led to a further increase in its affinity, Kd~3 nM. The IL-10R aptamer binds to IL-10 receptor on the cell surface and blocks IL-10 function in vitro, as shown by its ability to inhibit the IL-10 dependent proliferation of MC9 cells and rescue LPS mediated IL-12 secretion by DC in the presence of IL-10. Preliminary experiments suggest that intratumoral as well as systemic administration of the IL-10R aptamer was capable of inhibiting tumor growth in mice. On a molar basis the IL-10R aptamer was at least as potent as a corresponding antibody, both in vitro and in vivo.
Interleukin 21-activated B cells can kill tumor cells in a granzyme B-dependent manner (66.5)
Authors: Brüggemann Sabine , Kaltenmeier Christof , Hagn Magdalena , Sontheimer Kai , Dahlke Karen , Beyer Thamara , Lunov Oleg , Fabricius Dorit , Tron Kyrylo , Nienhaus Uli , Simmet Thomas , Jahrsdörfer Bernd 
Published: January 2023

Abstract
Interleukin 21 (IL-21) is a promising cytokine for the treatment of tumors and infections. Recently, IL-21 was identified as an inducer of plasma cells when combined with CD40 ligand (CD40L). Using various immunological methods including FACS analysis, ELISA, ELISpot and fluorescence microscopy, we demonstrate here that in the absence of CD40L B cells (BC) rather differentiate into granzyme B (GzmB)-secreting cytotoxic cells instead of plasma cells. GzmB induction in BC requires IL-21 and BC receptor cross-linking, and is associated with phosphorylation of SYK, JAK1/3 and STAT1/3, signaling molecules which are also involved in the activation of CTL and NK cells. CD40L effectively suppresses GzmB in BC, suggesting that GzmB-secreting BC play a role early during inflammatory responses, before CD40L-expressing T cells are present. BC-derived GzmB is enzymatically active and induces apoptosis in tumor cell lines including HeLa cells and PC3 cells. Importantly, induction of apoptosis by GzmB-secreting B cells can be suppressed by neutralization of GzmB using the substrate inhibitor Ac-IEPD-CHO as well as a novel small molecule inhibitor of GzmB identified in our laboratory. Our data reveal a novel role of IL-21-activated BC, which involves GzmB secretion and cytotoxicity. Our findings may have implications for the understanding of tumor immunosurveillance and early anti-viral immune responses, and may open novel approaches for the immunotherapy of neoplastic and viral diseases.
Sindbis virus suppresses Akt/mTOR signaling late during infection and induces mTOR independent antiviral response in HEK293T cells (67.12)
Authors: Mohankumar Vidyarani , Dhanushkodi Nisha , Raju Ramaswamy 
Published: January 2023

Abstract
Sindbis (SIN), an alphavirus has potent oncolytic properties and mTOR specific inhibitors are tested in combination with oncolytic viruses. Our aim was to study the effect of SIN replication on PI3K/Akt/mTOR signaling and its possible implications on innate antiviral response. In the presence and absence of PI3K/ mTOR inhibitors, HEK 293T cells were infected with SIN and UV-SIN. Replication of SIN was unaltered by the presence of inhibitors Ly294002, rapamycin and torin1 and rather suppressed phosphorylation of Akt, mTOR, S6 and 4E-BP1 late during infection. Currently, we are focusing on the effect of SIN infection on Akt phosphorylation in response to a subsequent growth stimulus in serum starved cells. PI3K/Akt pathway is required for IRF3 phosphorylation and expression of antiviral genes, which led us to study the regulation of these factors during SIN infection in the presence of inhibitors. Increased IRF3 phosphorylation and higher mRNA levels for ISG56 and IP-10 were seen with high intracellular viral RNA late during infection. Rapamycin and torin1 upregulated these antiviral responses, whereas prolonged Ly treatment partially blocked them. These results suggest that activation of IRF3 by SIN may be independent of mTOR, but partially dependent on PI3K/Akt. The potent inhibition of Akt/mTOR signaling by SIN may find applications in counteracting cellular drug resistance to kinase inhibitors and foster studies on engineered SIN genotypes in combination therapies.
Role of IL-12b in the regulation of viral pathogenesis in the respiratory tract (67.15)
Authors: Chakraborty Krishnendu , Lancelin Wallissa , Zhou Zehua , Wakamatsu Nobuko , Guerrero Plata Antonieta 
Published: January 2023

Abstract
Human metapneumovirus (hMPV), a newly-recognized member of the Paramyxoviridae family, mediate serious lower respiratory tract illness in very young children, the elderly and immunocompromised patients. The mechanisms that regulate the host immune response to hMPV are largely unknown. IL-12b is an important mediator in limiting lung inflammation and Th2 responses. However, the relative contributions of IL-12b to viral pathogenesis have not been extensively studied. We have observed that hMPV infection induces a robust and sustained production of IL-12b in the lung of infected mice beyond the resolution phase, suggesting that this cytokine plays an important role in hMPV infection. Using an IL-12b deficient (IL-12 KO) mouse model of infection we determined the role of IL-12b in hMPV pathogenesis. Our data indicate that the absence of IL-12b increased the disease severity in the course of hMPV infection as indicated by a significant increase in body weight loss (&gt;20%) in deficient mice when compared to WT animals. In addition, a three-fold increase in airway resistance, measured in artificially ventilated conditions by the Flexivent system was observed in the IL-12b KO mice. Furthermore, relative to WT mice, an altered CD4+ and CD8+ T cell responses in lung and draining lymph nodes was observed in hMPV-infected IL-12b KO mice. In conclusion, these findings indicate that IL-12b plays a regulatory role in disease pathogenesis and immune responses in the course of hMPV infection.
PD-1 blockage reverses immune dysfunction and viral persistence to Hepatitis B virus infection in mouse animal model (67.16)
Authors: Hsu Ping-Ning , Tzeng Horng-Tay , Liao Hsiu-Jung 
Published: January 2023

Abstract
Recent studies in animal models of virus infection, indicate that the interaction between the inhibitory receptor programmed death (PD)-1 on lymphocytes and its ligands plays a critical role in T-cell exhaustion by inducing T-cell inactivation, and high PD-1 expression levels on peripheral T-lymphocytes as well as the possibility to improve the T-cell function by blocking PD-1-mediated signaling to confirm the importance of this inhibitory pathway in inducing T-cell exhaustion. We studied T-cell exhaustion and the effects of PD-1/PD-L1 blockade on intrahepatic infiltrating T cells in our recently developed mouse model of hepatitis B virus (HBV) persistence with hydrodynamic injection of HBV DNA. In this mouse animal model, we demonstrated that there were increased intrahepatic PD-1 expressing CD8+ T cells and increased CD4+ FoxP3+ T cells in the mice with HBV persistence. Blockade of PD-1/PD-L1 interaction increased HBcAg-specific IFN-gamma production in intrahepatic T lymphocytes. Furthermore, blocking the interaction of PD-1 with its ligand PD-L1 by anti-PD-1 mAb reversed the viral persistence to clearance of HBV viral constructs in vivo. Our results indicated that PD-1 blockage reverses immune dysfunction and viral persistence to HBV infection in mouse animal model, suggesting anti-PD-1 mAb might be a good therapeutic candidate for chronic HBV infection.
Differential effects of blocking PD-1/PDL1 interaction in enhancing virus specific CD8 T cell response in young and aged mice (67.4)
Authors: Channappanavar Rudragouda , Twardy Brandon , Suvas Susmit 
Published: January 2023

Abstract
In this report, we compared the impact of blocking PD-1/PDL1 interaction to the virus specific CD8 T cell function in young and old C57BL/6 mice. Anti-PDL1 mAb treatment at the time of foot-pad HSV-1 infection to young C57BL/6 mice resulted in significantly increased proportion of SSIEFARL specific effector CD8 T cells in popliteal lymph node (PLN), spleen and PBMC. The frequency of IFN-γ, TNF-α and IL2, secreting SSIEFARL specific CD8 T cells was also increased in anti-PDL1 treated mice in comparison to isotype treated groups. An increased proportion of granzyme B expressing CD8 T cells were determined in PLN and spleen of anti-PDL1 treated mice. Interestingly, blocking of PD-1/PDL1 interaction at the time of CD8 T cell priming in young mice also improved the quality of HSV-1 specific memory CD8 T cell pool as noted by an enhanced recall response to SSIEFARL encoding vaccinia virus. On the contrary, blocking PD-1/PDL-1 interaction in aged mice increased SSIEFARL specific CD8 T cells only in PLN but not in spleen and PBMC. Moreover, frequency of effector molecules (IFN-γ, TNF-α, IL-2 and Granzyme B) expressing CD8 T cells did not change significantly in any of the collected tissues. Additionally, unlike in young mice, α-PDL1 treatment during priming failed to improve the quality of memory CD8 T cell response in aged mice. Taken together, we suggest that blocking of PD-1/PDL-1 interaction during priming enhance HSV-1 specific CD8 T cell response in young but not in aged mice.
Protective effect of IL-2 gene transfected cells against Salmonella infection in mice. (99.17)
Authors: Saito-Taki Tatsuo , Shimura Sayoko , Kanesaka Tomoyo , Onogawa Tsuyoshi , Kitasato Hidero 
Published: January 2023

Abstract
It is very hard to recover from lethal Salmonella infection in immunocompromized hosts by chemotherapy. Since the anti-bacterial activity of immunocompromized hosts is suppressed, immunomodulative therapy by immunostimulants such as adjuvant, cytokine, et al., is required. In this study, we used interleukin 2 (IL-2) as immunomodulator because IL-2 enhance cellular immune response via interferon γ production. As intracellular pathogen, Salmonella Typhimurium LT-2 infection induced Typhoid fever in mice. murine IL-2 gene transfered cell (C57/mIL-2) was prepared. Immunocompromized mice were inoculated with C57/mIL-2 cells before, simultaneous or after S. Typhimurium LT2 infection, and observed for 2 weeks about their viability. Protective effect of C57/mIL-2 was only observed cells were inoculated before LT2 infection. Now, more detail experiments to make clear the protective mechanisms by C57/mIL-2.
UVB-induced suppression of resistance to Mycobacterium tuberculosisin guinea pigs after BCG vaccination: cellular and molecular changes in the skin (99.19)
Authors: Jeevan Amminikutty , Formichella Cathryn , Russell Karen , Dirisala Vijaya 
Published: January 2023

Abstract
Previously, we reported that ultraviolet-B radiation (UVR) suppressed BCG vaccine-induced resistance to Mycobacterium tuberculosis in guinea pigs as it induced immuno-suppression and increased pathogenesis. In this study, we investigated the cellular and molecular changes within the guinea pig epidermis.The dorsal skin of guinea pigs was exposed to 5.6 kJ/m2 UVR and the epidermal cells were harvested 24 h later. Although UVR did not induce any gross morphological changes in the epidermis, a significant increase in the angular nucleated keratinocytes and a reduction in the number of cells with high nuclear to cytoplasmic ratio and binucleated cells were observed. Flow cytometry studies indicated that the proportions of CD3+ and CD4+ T cells increased in the epidermis while spleen showed a decrease in the CD3+, CD4+, CD8+, CD25+, MHC class II+ and CD14+ cells. Upregulation of IL-10, IL-4, IL-12p40, TGF-β, IL-1β and INOS mRNA expression was observed in the UV-irradiated epidermal cells. In addition, IL-4, IL-12p40, IFN-γ, and IL-1β mRNAs were increased in the spleen cells after UVR. Furthermore, culture supernatants from in vitro UV-irradiated keratinocytes reduced the MHC class II expression in the peritoneal cells and reduced the spleen cell proliferation to ConA. Future studies will address the identity of the suppressive factors induced by UVR and the systemic effect of culture supernatants from UV-irradiated epidermal cells on M. bovis BCG or M. tuberculosis infection.
Epitope-specific CD4+ T cell response to Group A Streptococcal infection (99.27)
Authors: Dileepan Thamotharampillai , Linehan Jonathan , Moon James , Pepper Marion , Jenkins Marc , Cleary Patrick 
Published: January 2023

Abstract
Group A Streptococcus (GAS) is the cause of a variety of clinical conditions, ranging from pharyngitis to autoimmune disease. Peptide-major histocompatibility complex class II (pMHCII) tetramers have recently emerged as a highly sensitive means to characterize pMHCII-specific CD4+ helper T cells. In lieu of identifying an immunodominant peptide expressed by GAS, a surrogate peptide (2W) was fused to the highly expressed M1 protein on the surface of GAS to allow in-depth analysis of the CD4+ helper T cell response in C57BL/6 mice. Following intranasal inoculation with GAS-2W, naïve 2W:I-Ab specific CD4+ T cells proliferated in the nasal-associated lymphoid tissues (NALT) and rapidly differentiated into cells that produced IL-17A. The acquisition of IL-17A production by 2W:I-Ab-specific T cells and the capacity of mice to survive infection depended on the innate cytokine IL-6. IL-6-deficient mice that survived infection became long-term carriers despite the presence of abundant IFN-γ-producing 2W:I-Ab specific CD4+ T cells. Experiments also revealed a unique consequence of multiple or recurrent infections; 2W:I-Ab T cells shifted from the IL-17A+ phenotype to a IL-17A+ IFN-γ+ (double positive) phenotype, cells associated with autoimmune disease in humans and rodent models; therefore, these findings could be key to understanding the chronic carrier stages and autoimmune complications to GAS infections in humans.