bluuebunny/crossref_metadata_2025_split huggingface dataset:
Naïve tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma (131.12)
Authors: Antony (PI) Paul , Xie Ying , Akpinarli Akgul , Maris Charles , Hipkiss Edward , Lane Malcolm , Kwon Eun-Kyung , Muranski Pawel , Restifo Nicholas 
Published: January 2023

Abstract
In vitro differentiated CD8+ T cells have been the primary focus of immunotherapy of cancer with little focus on CD4+ T cells. Immunotherapy involving in vitro differentiated T cells given after lymphodepleting regimens significantly augments antitumor immunity in animals and human patients with cancer. However, the mechanisms by which lymphopenia augments adoptive cell therapy and the means of properly differentiating T cells in vitro are still emerging. We demonstrate that naïve tumor/self-specific CD4+ T cells naturally differentiated into T helper type 1 (Th1) cytotoxic T cells in vivo and caused the regression of established tumors and depigmentation in lymphopenic hosts. Therapy was independent of vaccination, exogenous cytokine support, CD8+-, B-, NK and NK-T cells. Proper activation of CD4+ T cells in vivo was important for tumor clearance as naïve tumor-specific CD4+ T cells could not completely treat tumor in lymphopenic common gamma chain deficient (γc-/-) hosts. γc signaling in the tumor-bearing host was important for survival and proper differentiation of adoptively transferred tumor-specific CD4+ T cells. Thus, these data provide a platform for designing immunotherapies that incorporate tumor/self-reactive CD4+ T cells.
In vivo administration of artificial Antigen Presenting Cells licenses low avidity T cells for treatment of cancer (131.13)
Authors: Oelke Mathias , Ugel Stefano , Zoso Alessia , De Santo Carmela , Li Yu , Marigo Ilaria , Zanovello Paola , Scarselli Elisa , Cipriani Barbara , Bronte Vincenzo , Schneck Jonathan P. 
Published: January 2023

Abstract
The development of effective anti-tumor immune responses is normally constrained by low avidity, tumor-specific cytotoxic T lymphocytes (CTL) which are unable to eradicate the tumor. Therefore, new strategies to rescue anti-tumor activity of low avidity melanoma-specific CTL in vivo may improve immunotherapy efficacy. To boost the in vivo effectiveness of low avidity CTL we immunized mice bearing metastatic lung melanoma with artificial Antigen Presenting Cells (aAPC), made by covalently coupling pepMHC-Ig dimers and B7.1-Ig molecules to magnetic beads. aAPC treatment induced significant tumor reduction in a mouse telomerase antigen system and complete tumor eradication in a mouse TRP-2 antigen system, when low avidity CTL specific for these antigens were adoptively transferred. In addition, in an in vivo treatment model of subcutaneous melanoma, aAPC injection also augmented the activity of adoptively transferred CTL and significantly delayed tumor growth. In vivo tumor clearance due to aAPC administration correlated with in situ proliferation of the transferred CTL. In vitro studies showed that aAPC effectively stimulated cytokine release and TCR down-regulation in low avidity CTL. Therefore, in vivo aAPC administration represents a potentially novel approach to improve adoptive immunotherapy of cancer.
Development of an inducible MyD88.CD40 gene switch for potent anti-tumor dendritic cell (DC) vaccines (131.22)
Authors: Narayanan Priyadharshini , Lapteva Natalia , Seethammagari Mamatha , Slawin Kevin , Spencer David 
Published: January 2023

Abstract
We previously generated an inducible CD40 (iCD40) costimulatory switch enabling prolonged CD40 signaling in DCs in a ligand-independent manner. However, follow-up studies showed the requirement for an additional danger stimulus, lipopolysaccharide, for complete DC activation and licensing. To overcome drawbacks of systemic toxicity associated with endotoxin in a clinical trial, we proposed the development of a synthetic drug-inducible TLR4. Toward this goal, we have generated an inducible version of downstream adaptor MyD88 and combined it with iCD40 to generate a unified, inducible composite receptor, iMyD88.CD40. In vitro, in addition to upregulating maturation markers, iMyD88.CD40 activation by dimerizing drug led to elevated IL-12 production by both mouse and human DCs, prolonged DC survival and improved T cell responses to endogenous tumor antigens. Increased magnitudes of p38, IKK and JNK activation along with early activation of NF-kB family members, RelA, RelB and c-Rel form the molecular basis for the observed synergistic effects of iMyD88.CD40. In vivo, iMyD88.CD40-activated DCs migrated more efficiently to draining lymph nodes, promoted Th1 responses and abolished pre-established E.G7-OVA tumors and the less immunogenic B16 tumors. In conclusion, we have generated a novel chimeric DC activation switch combining signaling elements from adjuvant receptors enabling prolonged DC activation both ex vivo as well as in vivo following DC and drug delivery.
A persistent virus vector confers superior anti-tumor immunity,compared with a non-persistent vector (131.26)
Authors: Zhang Weijun , Zhang Tony , Turk Mary-Jo 
Published: January 2023

Abstract
Active vaccination strategies using viral vectors often give disappointing protection from tumor development, and usually require multiple immunizations. These approaches normally use viruses that cause acute infections, as they provoke potent CD8 T cell responses. Persistent virus vectors have not been used in this setting due to the perception that exhaustion of the T cell response occurs and would lead to poor anti-tumor protection. However, such exhaustion generally only occurs in high-load virus infections, whereas T cell function is intact in lower-load persistent infections. In fact, CD8 T cell responses in these infections, which are adapted for long-term immune surveillance,have properties that may make them more desirable for long-term anti-tumor immunity. In this report, we show that a persistent gammaherpesvirus vector provides superior protection against melanoma, relative to a nonpersistent mutant of the same virus. These data suggest that vaccine vectors derived from persistent viruses may perform better than those from acute viruses at mediating anti-tumor protection.
Targeting A2aR as a means of enhancing anti-tumor vaccines. (131.3)
Authors: Alme Angela , Senaldi Liana , Waickman Adam , Zarek Paul , Powell Jonathan 
Published: January 2023

Abstract
Adenosine, acting via the A2A adenosine receptor (A2aR), is emerging as an important inhibitor of immune function. Indeed, the tumor microenvironment contains relatively high levels of adenosine suggesting that tumor-derived adenosine is one mechanism by which cancers evade immune destruction. To better understand this potential mechanism of tumor immune evasion we challenged A2aR null mice with EL-4 lymphoma. In this model the A2aR null mice routinely rejected their tumors while Wildtype (Wt) mice succumb to tumor-induced death. Interestingly, while both Wt and A2aR null mice were able to reject low doses of tumor, when such mice were rechallenged with lethal doses of tumor, the A2aR mice were greatly protected compared to Wt controls. Such findings suggest that blocking the A2aR might greatly enhance the anti-tumor memory response. As such Wt and A2aR null mice were vaccinated with a whole cell GM-CSF secreting vaccine (GVAX) and challenged with B16 melanoma cells. In these experiments metastasis was markedly decreased in the untreated A2aR null mice when compared with untreated wt mice. Further, while the vaccine led to decreased metastasis in the Wt mice, the vaccine virtually eliminated lung metastasis in the A2aR null mice. Finally, pharmacologic blockade of the A2aR receptor in tumor-bearing mice promoted an increase in tumor antigen specific immunity. Overall, our data suggests that pharmacologic A2aR blockade can enhance the efficacy of tumor immunotherapy.
Activation of omental immune aggregates: a potential tumor therapy (131.37)
Authors: Sedlacek Abigail , Gerber Scott , Lord Edith 
Published: January 2023

Abstract
Tumor metastasis within the peritoneal cavity is a concern for those diagnosed with cancers of peritoneal organs. A tissue implicated in this process is the omentum, which is composed of adipose tissue embedded with immune cell aggregates. We, and others have demonstrated that upon introduction of tumor cells into the peritoneal cavity, omental immune aggregates are the initial site of attachment. Due to their high vascularity, they provide an ideal microenvironment for tumor growth. Thus, treatment of peritoneal metastases often includes removal of the omentum. However, we hypothesize that stimulation of omental immune cells might result in reduced tumor growth. Our initial experiments demonstrate that injection of particles into the peritoneal cavity resulted in their uptake by macrophages present in the peritoneal fluid and rapid migration to immune aggregates. To determine if tumor antigens would result in effective immunity when bound to these aggregates, mice were immunized intraperitoneally with irradiated EMT6 tumor cells and later challenged with live EMT6/GFP cells. Omenta and peritoneal fluid were analyzed for the presence of memory CD8+ T cells and tumor cells. Our results show that immunization results in increased memory CD8+ T cells and decreased tumor burden on the omentum, indicating that omental immune cells are capable of responding against tumor cells. Further studies are being done to examine tumor burden in mice immunized after tumor establishment.
Anti-melanoma immunity promoted by cutaneous genetic immunizations requires agonistic signaling via the nerokinin-1 receptor (131.6)
Authors: Mathers Alicia , Tkacheva Olga , Janelsins Brian , Schufeski William , Morelli Adrian , Larregina Adriana 
Published: January 2023

Abstract
In spite of initial enthusiasm provided by melanoma immunizations, the incidence of melanoma has increased in the past decade. To improve current melanoma vaccines is imperative that we understand the mechanisms involved in effective immunity to self-melanocyte Ags. The pro-inflammatory and immune functions of the skin are ideal for administration of cancer vaccines able to bias anti-tumor type-1 immunity. Pro-inflammatory neuropeptides that signal via the neurokinin-1 receptor (NK1R) expressed in skin cells, promote CD4+Th1 and CD8+Tc1 immunity to foreign Ag. Here, we analyzed the effects of signaling the NK1R during a skin genetic vaccination for melanoma. We utilized the gene gun to deliver plasmid DNA encoding murine TRP-2 with or without the NK1R agonist [Sar9Met O2)11]-SP (SarSP) to C57BL/6 mice. The need of the NK1R for anti-melanoma immunity was addressed by administration of our vaccine to NK1R-/- mice. GG immunizations in the presence of SarSP promoted TRP-2 immunity including short term-effector-, central- and effector- memory Th1 and CTLs resulting in the prevention of melanoma growth and long term survival of mice. Administration of TRP-2 vaccines to NK1R-/- mice showed an impaired ability to initiate anti-TRP-2 immunity. Our results shed light on the mechanisms involved in induction of self-Ag specific immune responses capable of overcoming tumor growth, and provide the foundation for the development of an effective melanoma vaccine.
The role of reactive oxygen intermediates (ROI) in B cell activation, proliferation, and differentiation (132.10)
Authors: Crump Katie , Grayson Jason 
Published: January 2023

Abstract
Reactive oxygen intermediates (ROI) are generated during mitochondrial respiration, receptor ligation, and microorganism digestion. Ligation of the BCR resulted in ROI production that reaches a maximum by 15 minutes. ROI can modify all macromolecules, but we are interested in reversible oxidation events that modulate signaling. Our focus is on cysteine sulfenic acid, the first cysteine oxidation product. Using 5,5 dimethyl-1,3-cyclohexanedione (dimedone), a compound that covalently reacts with sulfenic acid to prevent further oxidation or reduction, we addressed the role of reversible sulfenic acid formation in mature B cell activation, proliferation and differentiation. Following incubation with antibodies against surface bound Immunoglobulin M (IgM), mature B cells divide several times by three days. Incubation with dimedone results in a concentration dependent block of the initial division. This contrasted with dimedone-pretreated CpG DNA and LPS-stimulated B cells, where subsequent divisions were reduced compared to vehicle-treated cells. Dual stimulation with BAFF, CD40, and IL-4 did not rescue the effect of dimedone on proliferation. Cells pretreated with dimedone did not flux calcium when incubated with IgM, and in vitro plasma cell differentiation was also decreased. These studies demonstrate that mature B cell activation, proliferation and differentiation require reversible cysteine sulfenic acid formation.
The bone marrow environment maintains polyfunctional memory T cells during human aging (132.12)
Authors: Herndler-Brandstetter Dietmar , Landgraf Katja , Brunauer Regina , Jenewein Brigitte , Tzankov Alexandar , Keller Michael , Kloss Frank , Gassner Robert , Lepperdinger Günter , Grubeck-Loebenstein Beatrix 
Published: January 2023

Abstract
The bone marrow (BM) has recently been attributed a key role in memory T cell maintenance. However, little is still known about the distribution, phenotype and function of human T cell subsets in the BM and how aging affects BM T cell function and survival. Here we show that human BM T cells are in a heightened activation state and express a characteristic set of chemokine- and co-stimulatory receptors compared to peripheral blood (PB). BM T cells also rapidly proliferate upon stimulation with anti-CD3 and IL-15. Moreover, the number of polyfunctional CD4 and CD8 T cells was higher in the BM compared to the PB. Aging led to a decline of naive T cells and to an accumulation of cells with an effector/effector-memory phenotype in the BM. Though, the age-related increase in highly differentiated CD57-expressing effector CD8 T cells was much lower in the BM compared to the PB. During aging, the frequency of polyfunctional BM T cells was maintained. The expression of IL-6 was increased during aging in the BM and together with IL-15 might contribute to the sustained activation of memory T cells in the BM. Gene array analysis also revealed a potential cytokine network responsible for the age-related increase in IL-6 expression. In conclusion, our results indicate that the BM environment is important for the maintenance of polyfunctional memory CD4 and CD8 T cells during human aging.
The A2A Adenosine Receptor regulates T cell effector and memory differentiation (132.13)
Authors: Waickman Adam , Powell Jonathan 
Published: January 2023

Abstract
The A2A adenosine receptor (A2A AR) plays a critical role in regulating immune system activation and tolerance. We hypothesized that A2AR blockade would enhance T cell responses to viral infection. Indeed, A2A AR-/- T cells demonstrate increased expansion in response to vaccinia infection when measured 5 days after infection, and in co-adoptive transfer experiments A2A AR-/- clonotypic cells out perform their WT clonotypic counterparts. Surprisingly, two weeks post infection such was not case. Instead we found fewer A2A AR-/- clonotypic cells. Interestingly, in spite of the fact that the vaccinia infection is cleared rapidly, the A2A AR-/- clonotypic cells appeared “exhausted” displaying markers of chronic activation and the inhibitory receptor PD-1. Unlike what was seen with the A2A AR-/- T cells, pharmacologic treatment of WT mice with an A2A AR antagonist during the 5 days post infection led to a marked increase recall potency. Overall, our data demonstrate a previously unappreciated role for adenosine and the A2aR in regulating effector cell expansion and memory differentiation. Consequently, pharmacologic A2A AR blockade selectively during the perivaccine period can lead to both enhanced effector and memory responses.
Origin of Thymic Adipocytes in Aging: Incidental to Thymopoiesis or Instigator of Immunosenescence? (132.22)
Authors: Dixit Vishwa , Youm Yun-Hee , Yang Hyunwon , Venkov Christo , Manley Nancy , Nielson Eric , Leff Todd , Vandanmagsar Bolormaa 
Published: January 2023

Abstract
Vishwa Deep Dixit, Yun-Hee Youm, Hyunwon Yang, Christo Venkov, Nancy R Manley, Eric Nielson, Todd Leff, Bolormaa Vandanmagsar By 50 years of age most of human thymus is replaced with adipocytes of unknown provenance and uncertain function. We investigated the lineage and mechanism of thymic adipocyte formation during aging and asked whether manipulating these pathways regulates thymic function. Using.We demonstrate that indelibly LacZ marked FoxN1 thymic epithelial cells transition to give rise to local tissue fibroblasts via the epithelial-mesenchymal transition(EMT)process. Importantly, we found an age-related increase in pro-EMT regulator FSP1 and pro-adipogenic transcription factor PPARγ in thymus. Consistent with these findings, a subset of FoxN1LacZ+ cells are FSP1+ with large unilocular lipid droplet, typical of adipocyte phenotype. Furthermore, aged FSP1.GFP reporter mice revealed that the sorted FSP1+ thymic fibroblasts lack TEC signatures and express PPARγ, indicative of adipogenic lineage commitment. Notably, overexpression of constitutive-active PPARγ in FSP1+ adipogenic lineage cells led to increased thymic adipogenesis and reduced thymopoiesis. Conversely, inhibition of EMT and thymoadipogenesis via anti-aging intervention, caloric restriction prevented thymic aging and immunosenescence. Future longevity studies using specific genetic manipulation of these pathways may provide a definitive answer to the puzzle of age-related thymic adiposity and involution.
Gene Signature of Memory CD8+ T cells Produced by Irradiated Plasmodium Sporozoite Immunization (132.28)
Authors: Tse Sze-Wah , Chen Yun-Chi , Cockburn Ian , Zavala Fidel 
Published: January 2023

Abstract
In murine malaria models, liver resident memory CD8+ T cells are important for protective immunity as they efficiently eliminate malaria infected hepatocytes in vivo. Further characterization of liver resident memory CD8+ T cells is therefore very crucial for the design of an effective anti-malaria vaccine. Here, we describe a microarray approach aims to elucidate the genes and pathways that may involve in the homing, function and differentiation of liver resident memory T cells. We compared the gene expression profiles of antigen specific CD8+ T cells sorted from liver and those from spleen of mice 30-45 days after immunization with irradiated Plasmodium yoelii sporozoites. Preliminary analysis suggests memory CD8+ T cells from liver and spleen have very distinct gene expression profiles. We found clusters of genes enriched in biological functions such as adhesion, metabolic process, cell cycle and signal transduction. The results suggest that CD8+ T cells reside in peripheral organs such as the liver, may have undergone a different program of development than those memory cells that reside in secondary lymphoid organs such as the spleen.
Chronic alcohol consumption compromises NK cell release from the bone marrow and impairs NK cell maturation in the spleen (132.32)
Authors: Zhang Hui , Zhu Zhaohui , Meadows Gary 
Published: January 2023

Abstract
NK cells primarily originate in the bone marrow (BM). The release of these cells from BM to peripheral organs is associated with the sphingosine 1-phosphate (S1P) and S1P receptor 5 (S1PR5) signaling system. T-bet controls the expression of S1PR5 on NK cells. Chronic alcohol consumption inhibits splenic NK cell cytolytic activity and compromises NK cell release from the BM. The underlying mechanism is still unknown. Herein, we used a murine model to study the effects of chronic alcohol consumption on NK cell development in BM and spleen. Alcohol consumption increased NK cells in the BM. The increased cells were CD27hiMac-1hi. The expression of S1P5 and T-bet in splenic and BM NK cells did not change in the alcohol consuming mice. The number of NK cells in the spleen was significantly decreased. The decreased NK cells were CD27loMac-1hi. The percentage and numbers of the activating receptor, Ly49D and Ly49H, positive NK cells decreased significantly. However, the decrease in the percentage and number of the inhibitory receptor, Ly49G, Ly49C, and Ly49A, expressing NK cells was lower than the activating receptor positive NK cells. These results indicate that chronic alcohol consumption blocks NK cell release from BM at the CD27hiMac-1hi stage. The block is independent of T-bet and S1PR5 expression. The results also indicate that alcohol consumption inhibits terminal maturation of NK cells before they acquire activating Ly49 receptors in the spleen.
RANK-L expression marks long-lived plasma cells (132.5)
Authors: Quinn William , Stohl William , Choi Yongwon , Cancro Michael 
Published: January 2023

Abstract
Plasma cells (PC) are the effectors of humoral immunity. Short-lived PC are generated rapidly after either thymus-independent (TI) or thymus-dependent (TD) immunization, yielding low affinity antibodies associated with early primary immune responses. In contrast, the lasting protective titers of isotype switched, high affinity antibodies associated with TD responses are maintained by long-lived PC. These cells persist indefinitely in the bone marrow (BM), suggesting that unique homing properties, survival requisites, and stromal interactions may underlie their protracted survival. Herein we show that TD PC express Receptor Activator for Nuclear Factor κ B Ligand (RANK-L, also termed TRANCE), whereas TI generated PC do not. In addition, in vivo administration of RANK-Fc leads to a profound reduction in pre-existing long-lived plasma cell pools, and prevents the establishment of long-lived PC following primary immunization. Further, mixed bone marrow chimeras in which B lineage cells lack RANK-L display marked impairment in the generation of isotype switched splenic and BM PC following TD immunization. Finally, RANK-L expression enables TD PC to induce APRIL production by myeloid cells, which in turn fosters PC survival. Together, these findings reveal a novel circuit whereby RANK-L-expressing PC both induce and maintain their own survival niche, and establish RANK-L as a definitive marker for long-lived PC and their progenitors.
Role of G-protein Coupled Receptor Kinases GRK2 and GRK3 in C3a Receptor Signaling in Human Mast Cells (133.12)
Authors: Guo Qiang , Subramanian Hariharan , Ali Hydar 
Published: January 2023

Abstract
Studies with animal models have shown that complement components C3a and C5a play an important role in the effector phase of allergic asthma. We have previously shown that C3a activates human CD34+-derived mast cells to induce degranulation. To determine the role of GRKs on C3a receptor (C3aR) signaling in human mast cells, we used shRNA to knockdown GRK2 and GRK3 a human mast cell line, HMC-1 and CD34+-derived cultures of primary mast cells. We found that GRK2 and GKR3 knockdown inhibited C3aR desensitization as measured by enhanced C3a-induced Ca2+ mobilization in HMC-1 cells and greater degranulation in CD34+ mast cells but had no effect on receptor internalization. In addition, GRK3-knockdown in HMC-1 cells showed increased expression of cell surface C3aR and this was correlated with enhanced extracellular-signal-regulated kinase (ERK) activation and a four-fold increase in C3a-induced chemotaxis. Surprisingly, there was no enhancement of these responses in GRK2 knockdown mast cells. These findings suggest that while GRK2 and GRK3 are required for C3aR sensitization, presumably by promoting receptor phosphorylation, they play distinct roles in modulating downstream signaling such as ERK phosphorylation and chemotaxis.