bluuebunny/crossref_metadata_2025_split huggingface dataset:
A single pair of CD4+ and CD8+ T cell epitopes can induce protective T. cruzi immunity (39.56)
Authors: Zhang Xiuli , Eickhoff Chris S. , Sullivan Nicole L. , Hoft Daniel F. 
Published: January 2023

Abstract
Both CD4+ and CD8+ T cells are required for immunity protective against the protozoan parasite, Trypanosoma cruzi. The unique T. cruzi trans-sialidase (TS) antigen can induce both mucosal and systemic protection. BALB/c mice develop CD8 responses directed against the H2-Kd-restricted TS epitope IYNVGQVSI (aa 359-367). We have used overlapping peptides (18mers with 15 aa overlaps) spanning the TS amino-terminus (aa 33-275) to identify an H2-IAd-restricted CD4 epitope that induces potent TS-specific Th1 responses (KVTERVVHSFRLPALVNV; aa 58-75). Here we demonstrate that dendritic cells (DC) pulsed only with KVTERVVHSFRLPALVNV and IYNVGQVSI can induce potent protective immunity. DC generated in vivo with flt3-ligand were pulsed with 50 ug/ml of each peptide and injected intravenously into BALB/c mice (1 million/mouse) 3 times at 2 week intervals. One month later these mice were challenged with 5000 Tulahuén blood form trypomastigotes. Controls included unvaccinated mice and mice given DC only. Both parasitemia and mortality were significantly reduced (p&lt;0.05) in mice receiving DC pulsed with the TS peptides. These results indicate that monospecific CD4+ and CD8+ T cells can protect against a complex parasitic pathogen. We are preparing transgenic mice expressing TCR specific for these two epitopes with the goal of assessing in detail the mechanisms involved in the development of protective T. cruzi immunity.
This work was funded by NIH RO1 #AI040196 awarded to DFH.
Anti- and pro-tumor activities of the TLR2 ligand FSL-1 (40.2)
Authors: Shibata Ken-ichiro , Kiura Kazuto , Hasebe Akira , Iyori Mitsuhiro , Haque Mohammad Shamsul , Ohtani Makoto 
Published: January 2023

Abstract
The TLR2 ligand FSL-1, a mycoplasmal diacyllipopeptide, possessed TLR2-mediated anti- and pro-tumor activities in vivo when immunized with and without tumor-associated antigens (TAAs), respectively. CpG DNA possessed the anti-tumor activity as described previously, but did not possess the pro-tumor activity when immunized with CpG DNA alone. The anti-tumor activity of FSL-1 was explained by induction of TAAs-specific CTLs, ADCC of NK cells and reduction of the number of CD4+ CD25+ FOXP3+ regulatory T cells (Treg) cells in the draining lymph node. CpG DNA also induced production of TAAs-specific CTLs and reduction of the number of Treg cells when immunized with TAAs, but did not induce ADCC of NK cells. The pro-tumor activity of FSL-1 was explained by enhancing the immunosuppressive activity of Treg cells in the microenvironment of tumor, because the immunization with FSL-1 alone, but not CpG alone, increased significantly the number of Treg cells in the draining lymph node of mice when compared with that of control mice.
Anti-tumor activity of vitamin C through the maintenance of IFN-producing dendritic cell (IKDC) population. (40.20)
Authors: Kong Joo Myoung , Bae Se Yeon , Kang Jae Seung , Lee Na Eun , Maeng Hyung Gun , Kim Hye Min , Hwang Young Il , Lee Wang Jae 
Published: January 2023

Abstract
Natural killer (NK) cells play an important role in elimination of altered self cell, such as tumor cells. Recently, vitamin C is an essential component for augmentation of NK cell activity, especially in cancer patients.
In this study, the effects of vitamin C on the anti-tumor activity of NKDC (CD49b+CD11c+NK1.1+) were investigated in Gulo(-/-) mice, which can not biosynthesize vitamin C like human beings. Body weight and the size of spleen of vitamin C depleted Gulo(-/-) mice was significantly decreased at 2 weeks after vitamin C depletion, comparing to those of wild type or vitamin C-supplemented Gulo(-/-) mice. To investigate the function of NKDC, CD49b+cells from splenocytes were isolated by MACS and then analyzed by flow cytometry. As a result, the number of NKDC population was completely reduced in vitamin C depleted Gulo(-/-) mice, which showed decrease of a secretion of IFN-gamma ƒ×. In addition, Fms-like tyrosine kinase 3 ligand (Flt3L), which stimulates the expansion and differentiation of IKDCs, was significantly reduced in vitamin C depleted Gulo(-/-) mice serum. Finally, the anti-tumor function of splenocytes from vitamin C depleted Gulo(-/-) mice was decreased, compared with those of wild type or vitamin C supplemented Gulo(-/-) mice. Taken together, it suggests that vitamin C shows their anti-tumor activity through the maintenance of Flt3L and the number of IKDC population.
Cell cycle arrest and apoptosis induced by engagement of B7-H4 on EBV-positive B lymphoma cells (40.21)
Authors: Hur Dae Young , Park Ga Bin , Song Hyunkeun , Kim Yeong-Seok , Sung Minjung , Lee Hyun-Kyung , Lee Wang Jae 
Published: January 2023

Abstract
B7-H4 is a recently discovered B7 family member that has inhibitory effect on T cell immunity. However, the signaling mechanism of the B7-H4-expressing cells remains unclear. Previous work has shown that B7-H4 expression was enhanced on B cells by infection of Epstein-Barr virus (EBV), and engagement of induced B7-H4 exerted cell death of EBV-transformed B cells. Here we found that B7-H4 was constitutively expressed on EBV-positive Burkitt¡ s lymphoma cells and that engagement of B7-H4 significantly reduced cell viability of Raji cell. Engagement of B7-H4 resulted cell cycle arrest at G0-G1 phase in a dose- and time-dependent manner. To clarify the mechanism of B7-H4 triggering induced cell cycle arrest, cell cycle regulatory factor was examined by RT-PCR and immunoblotting. B7-H4 triggering down-regulated CDK4/6 and up-regulated p21 expression at both protein and RNA level. Furthermore, CDK2 and cyclineE/D expression was down-regulated by B7-H4 triggering. Additionally, the down-regulation of phospho-AKT and phospho-cyclinE was clearly detected in B7-H4 triggering Raji cells, but the phosphorylation of p53 was constitutively maintained. These results represent that B7-H4-mediated signaling on EBV-positive B cells modulates cell cycle through down-regulation of AKT pathway. We conclude that B7-H4 may have the potency for use in EBV-associated cancer therapy.
Characterization of T cell responses specific for a self-antigen expressed in the mouse prostate (40.23)
Authors: Chou Cassie K , Teague Ryan M , Tan Xiaoxia , Ratliff Timothy L , Greenberg Norman M , Greenberg Philip D 
Published: January 2023

Abstract
OBJECTIVE: Examine if functional prostate-specific T cells exist in mice and determine if such T cells might be harnessed for prostate cancer therapy.
METHODS: Studies were performed in transgenic mice (POET) expressing ovalbumin (OVA) under control of a prostate-specific promoter and double transgenic POETxOTI and POETxOTII mice, which contain OVA-specific CD8 or CD4 T cells, respectively.
RESULTS: Double transgenic mice revealed incomplete central deletion of OTI and OTII cells, with functional prostate-specific T cells still present in the periphery. To model the fate of prostate-specific T cells in which the self-protein is not expressed during development, we transferred OTI or OTII cells into POET mice. While most transferred OTI cells were deleted, the persisting OTI cells were antigen experienced and capable of expanding and inducing prostate inflammation. Transferred OTII cells by contrast maintained a naïve and responsive phenotype.
CONCLUSIONS: Antigen experienced prostate-specific CD8 T cells persist, can be induced to expand and infiltrate the normal prostate, and thus may prove useful for cancer therapy. CD4 T cells specific for the same prostate antigen remain naïve, suggesting limited presentation by APC. We are generating TRAMPxPOET mice, which develop OVA-expressing prostate cancer, to study targeting self-antigens for tumor therapy.
Supported by the NCI & a CRI Predoctoral Fellowship
HSP90 inhibitor 17-DMAG enhances EphA2+ tumor cell recognition by specific CD8+ T cells (40.27)
Authors: Kawabe Mayumi , Mandic Maja , Taylor Jennifer , Vasquez Cecilia , Wesa Amy , Neckers Leonard , Storkus Walter 
Published: January 2023

Abstract
EphA2, a member of receptor tyrosine kinases (RTK), is commonly expressed by a broad range of cancer types, where its level of (over)expression correlates with poor clinical outcome. Since tumor cell expressed EphA2 is a non-mutated "self" protein, specific CD8+ T cells are subject to self-tolerance mechanisms and typically exhibit only moderate-to-low functional avidity, rendering them marginally competent to recognize EphA2+ tumor cells in vitro or in vivo. We have recently reported that the ability of specific CD8+ T cells to recognize EphA2+ tumor cells can be augmented after the cancer cells are pretreated with EphA2 agonists that promote proteasomal degradation (Wesa et al., J. Immunol., in press, 2008). In the current study we show that treatment of EphA2+ tumor cells with the HSP90 inhibitor, 17-DMAG, similarly enhances EphA2 degradation by the proteasome, minimally impairs MHC class I antigen presentign machinery, and increases tumor cell recognition by specific CD8+ T cell lines and clones in vitro. These studies suggest that EphA2 represents a novel HSP90 client protein and that the treatment of cancer patients with 17-DMAG-based "pulse" therapy may improve the anti-tumor efficacy of CD8+ T effector cells reactive against EphA2-derived epitopes.
KIR receptors implicated in NK cell activation provide a risk of developing breast cancer (40.29)
Authors: Ashouri Elham , Farjadian Shirin , Ghaderi Abbas , Rajalingam Raja 
Published: January 2023

Abstract
The polymorphic killer-cell immunoglobulin-like receptors (KIR) are the key receptors of human NK cells that trigger early immune response against infection and tumors. To investigate if certain KIRs are associated with the development of breast cancer, we determined the KIR gene content in 153 women with breast cancer and 248 healthy controls. Frequency of group-B haplotypes that possess 2-6 activating KIR genes was predominant in patients compared to controls (60.8% vs. 42.3%, P = 4.9x10-7; 95% CI, 0.35-0.63, OR = 0.47). Particularly 3 activating KIRs that are associated with group-B haplotypes, 3DS1 (47.0% vs. 33.0%, P = 0.008; 95% CI, 0.37-0.85, OR = 0.57), 2DS1 (52.0% vs. 35.0%, P = 0.001; 95% CI, 0.34-0.77, OR = 0.51) and 2DS5 (43.0% vs. 25.4%, P = 0.0003; 95% CI, 0.29-0.69, OR = 0.45) were significantly increased in patients compared to controls. Moreover, 34% of the patients carried all these three KIRs compared to only 21.4% controls (P = 0.007; 95% CI, 0.33-0.83, OR = 0.52). We further observed a similar trend in patients with lung cancer, suggesting an universal tumor-susceptibility function for 3DS1- 2DS1-2DS5. Our data suggests that NK cells expressing activating receptors 3DS1, 2DS1 and/or 2DS5 may trigger an inappropriate localized hyperresponsiveness exacerbating the risk of cancer growth. Functional studies are underway to test if NK cells expressing KIR repertoire with and without these activating KIRs mount varied response against tumor lines.
Lipopolysaccharide treated murine mammary carcinomas secrete proinflammatory chemokines and exhibit reduced growth rates in vivo, but not in vitro (40.3)
Authors: Kurt Robert A , Nair Priyanka , O'Donnell Cara , Janasek Karolina , Sajduk Monika , Smith Emily , Golden Jacqueline , Vasta Casey , Huggins Alison 
Published: January 2023

Abstract
Toll-like receptors (TLR) are pattern recognition receptors that play a pivotal role in the initiation of immune responses. Ligation of TLR on antigen presenting cells enhances immunological responses through multiple mechanisms including secretion of proinflammatory mediators. Here we report that the murine mammary carcinoma 4T1 constitutively expressed genes encoding TLR2, 3, 4 and 5. Moreover, treatment of 4T1 with peptidoglycan (PGN), polyinosinic-polycytidylic acid (Poly(I:C)) or lipopolysaccharide (LPS), agonists for TLR2, 3 or 4 respectively, induced nuclear translocation of NFkB and secretion of CCL2, CCL5 and CXCL1 in a dose dependent manner. Although treating the tumor cells with the TLR agonists did not modulate growth or viability of the tumor cells in vitro, 4T1 exhibited a decreased growth rate in vivo following treatment with LPS that was dependent upon the presence of CD8+ T cells. Analysis of three additional murine mammary carcinomas revealed that they also secreted CCL2, CCL5 and CXCL1 in response to TLR agonist treatment, and LPS treated 168 and SM1 tumors exhibited decreased growth rates in vivo, but not in vitro. These data indicated that four out of four murine mammary carcinomas secreted proinflammatory chemokines following treatment with TLR agonists, and three out of four of the mammary carcinomas responded to LPS treatment in a manner that decreased tumor growth in vivo.
Role of uridine kinase-like 1 (UCKL-1) in NK-mediated tumor cytotoxicity (40.9)
Authors: Ambrose Elise C , Kornbluth Jacki 
Published: January 2023

Abstract
NK lytic associated molecule (NKLAM), which is upregulated in NK cells by activation, has been shown to play a critical role in NK-mediated tumor cytotoxicity. We have found that NKLAM interacts with uridine kinase-like 1 protein (UCKL-1) and causes its ubiquitination and subsequent degradation. This suggests that NKLAM may play a role in tumor killing by decreasing UCKL-1 expression in target cells. In support of this is the finding that UCKL-1 mRNA is most abundant in tumor cell lines, indicating that it may be important in tumor cell growth and/or survival. In order to determine the function of UCKL-1 in tumor cell killing, K562 target cells were treated with UCKL-1 RNAi or control RNAi. Selective knockdown of UCKL-1 resulted in increased apoptosis and decreased proliferation of K562. In addition, decreased UCKL-1 expression increased the susceptibility of K562 to the apoptosis inducers staurosporine and etoposide. This finding indicates that UCKL-1 plays a role in the proliferation of K562 cells and protects them from apoptosis. By ubiquitinating and degrading UCKL-1 in target cells, NKLAM released from NK cells would therefore enhance tumor killing.
This research is supported by a merit review award from the Department of Veterans Affairs.
Analysis of in vivo homing of cytokine-induced killer cells into lymph nodes (41.17)
Authors: Han Sang-Bae , Kim Yeon Jin , Kim Jee Youn , Ryu Hwa Sun , Kim Hyung Suk , Yun Jun Ho , Kim Hwan Mook , Kang Jong Soon , Song Sukgil , Hong Jin Tae , Kim Youngsoo 
Published: January 2023

Abstract
The goal of immune cell-based cancer therapy is to eliminate cancer cells through the transfer of ex vivo expanded and activated immune cells. Cytokine-induced killer (CIK) cells are ex vivo expanded T cell mixture with proven anticancer activity in vitro and in vivo. In the presence of immobilized anti-CD3 antibody and IL-2 for 14 days, mouse splenocytes changed to heterogeneous CIK cell population, which comprised 97% CD3+, 86% CD8+, 7% CD4+, 25% CD3+NK1.1+, and 30% CD8+NK1.1+. Although CD3+NK1.1+ cells were rare in fresh human peripheral blood mononuclear cells, they could expand more than 1,000-fold on day 14. Ex vivo proliferation of splenocytes was critically dependent on IL-2 concentration and cell density; in that IL-2 was required at least 750 U/ml and cell number was maintained at one or two million cells per milliliter during the cultivation. CIK cells strongly expressed IFN-gamma and IL-2, moderately IL-4 and TNF-alpha, but not IL-1beta, IL-5, and IL-10. Compared with purified T cells, CIK cells also expressed lower levels of adhesion molecules, such as L-selectin and CD49d, and chemokine receptors, such as CCR7 and CXCR4. It was resulted in less trafficking of CIK cells to lymph nodes than purified T cells did, which was determined by confocal microscopic and flow cytometric analysis. The data shown here demonstrated that inappropriate trafficking of CIK cells to lymph nodes might be one of the hurdles for in vivo application of CIK cell therapy, and suggest that L-selectin, CD49d, CCR7 and CXCR4 might be good targets to increase CIK cell trafficking to lymph nodes.
Increase of antigen expression and activation of APCs by targeting adenovirus to CD40 significantly enhanced therapeutic effect of antigen presenting cell-based anti-tumor vaccine (41.18)
Authors: Kim Yun-Sun , Han Seung-Hee , Kim Yeon-Jeong , Ko Hyun-Jeong , Park Hae-Jung , Pereboev Alexander V. , Nguyen Huan H. , Kang Chang-Yuil 
Published: January 2023

Abstract
The efficacy of antigen presenting cell (APC)-based vaccines generated in vitro by genetic transduction critically depends on the expression level of target antigen and the activation status of APCs. Although APCs such as DCs and B cells transduced by recombinant adenovirus (AdV) readily induced antigen specific immune responses, they are relative resistant to adenoviral transduction due to the lack of coxsackievirus-adenovirus receptor (CAR), which mediates adenovirus entry. In this study, we used recombinant adapter molecule, CFm40L, which consists of CAR genetically fused to CD40 ligand via a trimerization motif, to target Her-2/neu or HPV16 E6/E7-encoding AdV to DCs and B cells that express CD40. Such transduced DCs and B cells enhanced substantially immunity against Her-2/neu or HPV16 E6/E7-expressing tumor resulted in significant inhibition of tumor growth. Especially, the anti-tumor effect of B cell-based vaccines transduced with CD40-targeted adenoviral vector is comparable to that of DC-based vaccines, indicating the feasibility of B cell-based vaccine for anti-cancer therapy. Our results suggest that targeting AdV to APC via CD40 using CFm40L offers a novel approach in anti-tumor therapy
Ex vivo induction and expansion of Natural Killer T cells by CD1d1-Ig coated artificial antigen presenting cells (41.22)
Authors: Webb Tonya J , Bieler Joan G , Schneck Jonathan P , Oelke Mathias 
Published: January 2023

Abstract
Natural killer T (NKT) cells play a pivotal role in maintaining immune homeostasis. Many studies examining patients with cancer have shown that there is a reduction in both NKT cell number and function. Due to the complexities of manipulating NKT cells in vivo, ex vivo expanded effector NKT cells would be an excellent therapeutic modality. To date, immunotherapy utilizing the NKT/CD1d system has been dependent on the use of autologous antigen presenting cells pulsed with α-galactocylceramide (α-GalCer). In this study, we have generated CD1d- expressing artificial antigen presenting cells (aAPC) to examine co-stimulatory requirements for NKT cells and to expand NKT cells from the peripheral blood of healthy controls and cancer patients. We tracked the level of NKT cell expansion and the expanded population was characterized both phenotypically and functionally. We found that CD1d-based aAPC can effectively propagate both canonical (iNKT cells) and noncanonical NKT cells. Thus, CD1d-expressing aAPC will enhance our knowledge of NKT cell biology and could potentially be used as a novel tool in adoptive immunotherapeutic strategies.
Chimeric Antigen Receptors for Stem Cell Based Immunotherapy (41.23)
Authors: Badowski Michael S , Tsang Tom C , Zhang Tong , Harris David T 
Published: January 2023

Abstract
Chimeric antigen receptors (CARs) can provide anti-tumor specificity, and adoptive transfer of CAR-modified stem cells offers a method to introduce and expand tumor specific T-cells. This adoptive immunotherapy can eliminate malignant cells or supplement traditional therapies. The use of a single chain TCR (scTCR) in which the TCR Vα and Vβ segments are joined by a flexible linker provides a better alternative to introduction of full length TCR genes. We have developed a HER2 specific scTCR as well as a single chain antibody based receptor (scFv) to increase avidity to the tumor antigen and avoid the potential limitation of MHC restriction. Our lab has previously developed a signaling cassette based on the CD28 and p56Lck proteins which are prominent in the T-cell signaling pathway. The single chain specificities are linked to the signaling cassette that we have shown to function in T-cells. With specificity and signaling coupled, the chimeric antigen receptor can be transduced into hematopoietic stem cells (HSC). Engraftment of the transduced HSC shows multiple cell types expressing our transgene reporter. Anti-tumor activity of transduced cells is measured by cytokine release upon stimulation.
Targeting Lymphoma with Bispecific Antibody-Armed T Cells and their Potential for use in an Allogeneic Setting (41.31)
Authors: Cousens Leslie  P. , Davol Pamela A. 
Published: January 2023

Abstract
Patients with high-risk refractory or relapsed lymphomas face a poor prognosis and limited therapeutic options. Current treatment regimens of chemotherapy with either rituximab (anti-CD20 mAb) or with allogeneic stem cell transplant (alloSCT) yield serious toxicities and high relapse rates. In particular, benefits of alloSCT are grossly limited by life-threatening graft vs host disease (GvHD). New approaches to enhance graft vs lymphoma (GvL) effects without increased GvHD are needed. Bispecific antibodies (BiAbs) are produced by linking anti-CD3 for T cell binding to an antibody specific for a tumor antigen. Anti-CD3 activated T cells (ATC) "armed" with BiAb express tumor-specific CTL function independent of further activation, proliferation, antigen presentation or costimulation. Studies here examined allo-reactivity of BiAb-armed ATC for potential application in an allogeneic setting. Data show that ATC armed with anti-CD3 x anti-CD20 BiAb specifically target and kill B cell lymphomas. However, BiAb-armed ATC are remarkably poor stimulators of, or responders to, allo-stimlulation. These results provide important evidence of a functional separation between the GvL and GvH effects of BiAb-armed ATC.
Differential expression of CD4+ TReg cell subpopulations among ovarian cancer patients following autologous MUC1-specific Th1 effector cell immunotherapy (41.38)
Authors: Dobrzanski Mark J , Rewers-Felkins Kathleen , Samad K.A. , Robinson William , Wright Stephen E 
Published: January 2023

Abstract
Adoptive T cell immunotherapy is a viable treatment for cancer patients and optimally requires participation of Ag specific CD4 T cells. Here, we assessed the therapeutic effects of adoptively transferred autologous MUC1 peptide stimulated CD4+ effector cells in patients with ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4+/Th1 effector cell generation, we show that 3 monthly treatment cycles of T cell restimulation and intraperitoneal re-infusion modulated T cell mediated immune responses that correlated with diminished serum CA125 tumor marker levels and enhanced patient survival. One patient survived long term (&gt;5 yrs), another patient survived long term with recurrent disease (&gt;5 yrs) and two patients expired within 100 days following final infusion. Long term survivors showed elevated levels of systemic memory (CD45RO) and naïve (CD45RA) CD3/CD4/CD25+ T cells. Such cells co-expressed different levels of Foxp3 and CTLA-4 that resulted in lower systemic Foxp3/CTLA-4 memory T cell ratios. Lastly, these patients showed elevated levels of MUC1 specific T cells expressing the CCR5 and CCR1 chemokine receptors associated with T cell differentiation and select migration. This data suggests that effective immunotherapy with autologous MUC1 peptide-stimulated CD4+ effector cells induce differential levels of systemic TReg cell subpopulations that influence long term tumor immunity in ovarian cancer patients following adoptive T cell transfer.