bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunomodulator AS101 potentiates apoptosis on Ha-Ras transformed cells which correlates with suppression of a survival protein Akt (48.20)
Authors: Sredni Benjamin , Eliyahu Siona , Lander Harry , Albeck Michael , Segal Shraga 
Published: January 2023

Abstract
The Ras family is the most widely mutated group of human proto-oncogene. Previously, we found an organic Tellurium compound, AS101, which exhibits immunomodulatory activity and strong anti-tumor effects. Whether these properties can be exploited for cancer therapy was examined using v-Ha-Ras transformed and V-mos transformed fibroblasts cells. In this study AS101 appeared to selectively block ~90 % of the proliferative growth of v-Ha-Ras transformed cells, while not affecting the growth of V-mos transformed cells. Furthermore, the proliferative growth inhibiting effect of AS101 was prevented when the activity of p21Ras was blocked by expression of a dominant negative mutant 116y of the v-Ha-Ras or by treating Ha-Ras transformed cells with a farnesyltransferase inhibitor. The anti-proliferative effect of AS101 was accompanied by morphological changes typical of apoptosis i.e.: membrane blebbing, condensation of nuclear chromatin, and formation of apoptotic bodies. AS101-induced apoptosis of v-Ha-Ras transformed cells correlated with suppression of Akt protein expression, activation of caspases, and induction of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1. Thus, our results suggest that AS101 can be used to effectively treat tumors which, are induced due to an oncogenic mutation in p21Ras encoding gene and to selectively block oncogenic function of mutated Ha-Ras in human tumors.
CpG DNA augments dendritic cell-based therapy of colon cancer in transgenic mice (48.21)
Authors: Saha Asim , Chatterjee Sunil K. , Foon Kenneth A. , Celis Esteban , Bhattacharya-Chatterjee Malaya 
Published: January 2023

Abstract
Induction of potent and sustained anti-tumor immunity depends on the efficient activation of CD8+ and CD4+ T cells. Immunization using dendritic cells (DC) loaded with tumor Ag has shown promising results in cancer immunotherapy. Recently we have reported that in DC based immunization protocol in therapeutic setting with 7-day-old established MC-38-CEA-A2Kb tumors, mice (transgenic for both CEA and HLA-A2) immunized with agonist peptide for CEA691 (YMIGMLVGV, peptide-1) or mice immunized with agonist peptide for CAP-1 (YLSGADLNL, peptide-2) along with 3H1 (anti-idiotype Ab mimicking CEA) induced significant increase in survival with complete tumor eradication in 50% and 67.5% of the mice respectively. In this study, we attempted to augment anti-tumor immunity by the combination of 3H1-pulsed DC plus peptide-1-pulsed DC or peptide-2-pulsed DC along with immuno-stimulatory CpG (ODN–1826) in a therapeutic setting. Co-administration of CpG ODN provided significant increase in tumor free survival compared with mice immunized with peptide-pulsed DC plus 3H1-pulsed DC alone. Combined vaccination with CpG ODN resulted in increased secretion of Th1 cytokines such as IFN-γ and TNF-α, and HLA-A2-restricted CEA-specific CTL responses were also enhanced. Thus, the combination of Ag-loaded DC and CpG ODN is an effective vaccination strategy for future clinical application.
Supported by the NIH grant RO1 CA104804.
HLA Class II Protein Expression in Prostate Cancer Cells (48.22)
Authors: Haque Azizul , Younger Austin R , Amria Shereen , Geffrey Whitney A , Goldstein Oliver G , Norris James S 
Published: January 2023

Abstract
Prostate cancer is the second most commonly diagnosed cancer in men. Presently, there is no effective treatment for patients who develop recurrence, or for those who have metastatic disease at the time of diagnosis. Recent evidence suggests that reduced expressions of target protein antigens as well as HLA molecules are the predominant immune escape mechanisms of malignant prostate tumors. The purpose of this study was to investigate the prospect of antigen specific immunotherapy against prostate cancer via the HLA class II pathway of immune recognition. Here, we show for the first time that prostate cancer cells express functional HLA class II proteins that are recognized by T cells. We also show that prostate cancer cells can be induced with IFN-γ to express high levels of class II proteins as well as an enzyme, lysosomal thiol reductase (GILT), that may facilitate enhanced class II antigen presentation and CD4+ T cell recognition. Select prostate tumors can be transduced with HLA class II molecules resulting in efficiently presented antigenic peptides that also stimulate CD4+ T cells. These data suggest that prostate cancer cells can be targeted via the HLA class II pathway, and that genetically manipulated prostate tumor cells can be employed for direct antigen presentation, and CD4+ T cell mediated tumor therapy.
IDENTIFICATION OF AN ANTIGENIC AND IMMUNOGENIC MOTIF EXPRESSED BY TWO 7-MER RITUXIMAB-SPECIFIC CYCLIC PEPTIDES. (48.26)
Authors: Perosa Federico , Favoino Elvira , Merchionne Francesca , Dammacco Franco 
Published: January 2023

Abstract
Two 7-mer cyclic peptides, bearing the antigenic motif recognized by the anti-CD20 mAb Rituximab and differing because of motif-surrounding amino acids, inhibit the binding of Rituximab to raft-associated CD20 and Rituximab-induced membrane ceramide on human lymphoid DAUDI cells. These peptides displayed different immunogenic profiles, in that antibodies recognizing CD20 were induced in two and five out of five BALB/c mice immunized with Rp-15-C and Rp13-C respectively. Analysis of immunogenic motif, performed by panning a 7-mer phage display peptide library with purified anti-peptide IgGs, showed that the motif defined by anti-Rp15-C mostly included amino acids surrounding the Rituximab-specific antigenic motif “ANPS”, whereas that defined by anti-Rp13-C was “NPS”. These data showed that the motif-surrounding amino acids can markedly influence the specificity of antibodies, even when elicited with a short 7-mer peptide. Since anti-peptides antibodies analyzed are IgG, their specificity is likely to reflect how peptides are processed at the T cell level and suggests that, within a short peptide, the motif defined by T cells during the recognition phase may be different from that recognized by these cells upon their stimulation. Our findings can explain the failure of most peptide-based immunotherapy in cancer and autoimmune diseases and suggest strategies to implement the specificity of peptides-induced antibodies against the target antigen
Engineering T cell receptors for potential therapeutic applications (48.28)
Authors: Richman S A , Aggen D H , Stone J D , Weber K S , Dossett M L , Donermeyer D L , Mariuzza R A , Allen P M , Greenberg P D , Kranz D M 
Published: January 2023

Abstract
Using T cell receptors (TCRs) for potential therapeutic applications provides an opportunity to target an expanded array of antigens, compared to those now targeted with monoclonal antibodies. Relative to antibodies, TCRs typically exhibit reduced solubility and lower affinity, properties that hamper their production and efficacy. To improve these parameters, we have developed strategies using yeast display engineering. Several different TCRs were cloned as single chain (sc) TCRs and VαCα/VβCβ heterodimers, as each of these display scaffolds has unique advantages for engineering and potential applications. Display of scTCRs, unlike that of scFv fragments, required mutagenesis and selection. Analysis of a collection of mutants revealed distinct regions of the scTCR that require mutations to allow yeast surface display, as well as solubility of purified protein. Although the sc format has several potential advantages such as increased tissue penetration, mutagenesis and selection of displayed mutants can present a technical challenge. To overcome this obstacle, we have recently explored the role of the C domains in driving heterodimer association. In addition, we have developed mutagenic strategies to improve the association of engineered, full λετ γη α and β chains.
Supported by grants from NIH.
Blockade of hyaluronan, a CD44 ligand, inhibits IL-2–induced vascular leak syndrome while maintaining effective treatment of melanoma (48.30)
Authors: Guan Hongbing , Nagarkatti Prakash S , Nagarkatti Mitzi 
Published: January 2023

Abstract
High-dose IL-2 therapy is an effective mode of treatment against melanomas; however, its use is limited by accompaniment of vascular leak syndrome (VLS), a life-threatening toxicity. The precise mechanism/s of VLS is unclear and there is no specific therapy to block VLS and enhance IL-2 based immunotherapy. Previous studies from our laboratory demonstrated that CD44 plays a critical role in VLS; administration of hyaluronan (HA), a primary ligand for CD44, caused a marked increase in IL-2 induced VLS. In this study, we report a novel means to prevent VLS by blocking endogenous HA with HA-specific binding peptide, Pep-1. Our results demonstrated that administration of Pep-1 into IL-2 treated mice dramatically inhibited IL-2-induced VLS in the lungs and liver. Interestingly, Pep-1 treatment did not affect the effectiveness of IL-2 in treatment of melanoma. Pep-1 treatment did not affect the emigration of lymphocytes across the endothelium and the activation of CTL seen during IL-2 treatment. Also, blocking HA with Pep-1 maintained endothelial integrity and prevented their apoptosis. Our results demonstrate that HA plays a role in regulating endothelial damage and blockade of HA could be a novel means for prevention and treatment of VLS thereby facilitating IL-2-induced immunotherapy of melanomas.
(Supported by NIH grants RO1 AI 053703, RO1 DA 016545, RO1 AI 058300, RO1 HL 058641 and RO1 ES 09098)
Adenovirus-human HER2 vaccine inhibits breast cancer growth and vaccine induced antibodies (VIA) are efficacious against Herceptin-refractory human breast cancer (48.32)
Authors: Wei Junping , Hartman Zachary , Osada Takuya , Yang Xiao Yi , Lei Gangjun , Jiang Haixiang , Chong Gabriel , Amalfitano Andrea , Lyerly H. Kim , Morse Michael , Clay Timothy 
Published: January 2023

Abstract
While HER2/neu specific antibody (Herceptin) therapy has clear efficacy against HER2 overexpressing tumors, most patients who initially respond to Herceptin show disease progression within one year despite continued high expression of HER2. As an alternative to Herceptin, we developed a novel set of adenoviral vectors encoding human HER2 which break tolerance and induce T and B cell responses in human-HER2-transgenic (HuHER2-Tg) mice (kindly provided by W-Z. Wei, Karmanos Cancer Center, MI). Ad-HER2 vaccination results in a high level of HER2-specific T cells and anti-HER2 vaccine induced antibodies (VIA), which significantly inhibits the growth of human HER2 expressing murine 4T1 breast cancer cells (kindly provided by M. Kershaw, Peter MacCallum Cancer Centre, Melbourne, Australia) in HuHER2-Tg mice. Anti-HER2 VIA strongly bound to Herceptin-refractory human breast tumor cells and significantly inhibited their growth in vitro, and mediated complement dependent cytotoxicity. Thus, our findings demonstrate that Ad-HER2 vaccination proved to be efficacious and therapeutically relevant in Herceptin refractory tumor models.
Grant support: NIH P50-CA068438 SPORE in Breast Cancer & DOD CTRA BC050221.
Friend or Foe? IFNγ Mediates Pro-Metastatic Gene Expression in the Tumor Microenvironment (48.34)
Authors: Hall Veronica L , Subleski Jeff , Back Tim C , Gruys M. Eilene , Shorts-Cary Lynnette , Weiss Jonathan M. , Wiltrout Robert H 
Published: January 2023

Abstract
Several immunotherapeutic models have shown that interferon gamma (IFNγ) is required for tumor regression. Treatment with IFNγ as a sole therapy, however, has resulted in disappointing outcomes. Cytokine therapies, such as IL-2/IL-12 and IL-12/IL-18, each involves IFN-γ mediated reduction in primary tumors but they can have an unanticipated increase in secondary metastases. Therefore, tumor responsiveness to IFNγ may alter its progression and metastasic potential. Mouse renal carcinoma cells expressing a dominant negative IFNγ-receptor had a reduced ability to metastasize, suggesting that IFNγ may exert potentially pro-metastatic effects in the tumor microenvironment. The goal of this study is to identify changes in gene expression in the tumor microenvironment in response to IFNγ treatment. Using qPCR gene profiling, we identified the increased expression of several pro-metastatic genes specifically in the tumor microenvironment after IFNγ treatment, namely heparanase, CD44, s100a4, and matrix metalloproteinase 7. We are now investigating whether the upregulation of these genes is caused by host and/or tumor responses to IFNγ. Our results suggest that IFNγ regulates extra-cellular matrix remodeling protein expression in the local microenvironment, which may contribute to tumor metastases.
Activity of Anti-PD-1 in Murine Tumor Models: Role of “Host” PD-L1 and Synergistic Effect of Anti-PD-1 and Anti-CTLA-4 (48.37)
Authors: Korman Alan , Chen Bing , Wang Changyu , Wu Linda , Cardarelli Pina , Selby Mark 
Published: January 2023

Abstract
PD-1, like CTLA-4, is a negative regulator of T cell function. The PD-1 ligand, PD-L1, is expressed by dendritic cells/antigen presenting cells and by activated T cells. Many tumors express PD-L1 and its expression has been linked to poor prognosis. PD-L1 expression is also upregulated by γIFN. We studied the activity of anti-PD-1 in two subcutaneous tumor models which differ with regard to PD-L1 expression: Sa1N fibrosarcoma, which is negative for PD-L1, and cannot be induced to express PD-L1 by γIFN; and, MC38 colon adenocarcinoma, which expresses low levels of PD-L1 which is upregulated by γIFN. Anti-PD-1 blockade resulted in partial tumor growth inhibition in both models demonstrating that the activity of anti-PD-1 is independent of PD-L1 expression on the tumor. This suggests that host PD-L1 (and/or PD-L2) expression limits anti-tumor activity. In the MC38 model, the concurrent use of anti-PD-1 and anti-CTLA-4 antibodies was significantly more potent than either of the individual antibodies or sequential administration of the antibodies regardless of order. These results are consistent with a role for PD-1 and CTLA-4 in T cell priming and suggest that they play non-redundant roles during T cell activation. Cell subsets implicated in the activity of PD-1 and CTLA-4 blockade in the MC38 model are under investigation.
Selective metalloproteinase inhibition of human CD30 shedding increases specificity of targeted immunotherapy (48.38)
Authors: Hansen Hinrich Peter , Simhadri Vijaya Lakshmi , Eichenauer Dennis , Ludwig Andreas , Engert Andreas , von Strandmann Elke Pogge 
Published: January 2023

Abstract
The receptor CD30 is selectively overexpressed on many human lymphoma cells and therefore an interesting target for antibody-based immunotherapy. However, binding of therapeutic antibodies stimulates CD30 shedding leading to a loss of target antigen and a release of the soluble ectodomain (sCD30). Here, we showed that sCD30 binds to membrane-anchored CD30 ligand (CD153) on mast cells and neutrophils which are frequently found among the bystander cells in lymphoma tissue. Using sCD30 as a linker, CD30 antibodies are able to bind to mast cells where they caused the release of interleukin-8 (IL-8) which is involved in angiogenesis and metastasis. To overcome this adverse shedding-dependent mistargeting we used loss-of-function experiments with cells lacking candidate CD30-releasing enzymes ADAM10 and ADAM17 and a selective inhibitor to identify ADAM10 as the main enzyme responsible for antibody-stimulated shedding. In co-culture experiments, the antibody-induced transfer of sCD30 from the human Hodgkin lymphoma cell line L540 to the CD30-negative but CD153-expressing human mast cell line HMC-1 was inhibited by the ADAM10-selective inhibitor GI254023X. These findings suggest that selective metalloproteinase inhibitors blocking antibody-induced shedding of target antigens could be of therapeutic value to increase the specificity and reduce side-effects of immunotherapy with monoclonal antibodies.
Overexpressed circulating serine proteases are a predominant source of self-antigen for potent T lymphocyte immunity to human leukemia (48.5)
Authors: Sergeeva Anna , Ono Yoko , Molldrem Jeffrey J 
Published: January 2023

Abstract
From the experience of clinical transplantation, cytotoxic T lymphocytes (CTL) mediate strong anti-leukemia immunity, although a little is known about the targets of that immunity. We identified an HLA-A2- restricted nonomer PR1 (VLQELNVTV) from proteinase 3 (P3) and neutrophil elastase (NE) that was recognized by CTL, that preferentially killed leukemia cells. To determine the protein source of PR1, we studied distribution of both P3 and NE in patients with AML and CML. Serum NE (ng/ml) assessed by ELISA was increased in 13 out of 14 AML patients and in 19 out of 20 CML patients, compared to that in 4 healthy donors (HD) (1055 ± 132, and 1002 ± 103 versus 54 ± 13; p = 0.0002 and p = 0.0006, respectively). In contrast, overexpression of serum P3 (ng/ml) in 19 AML patients and 28 CML patients was not significantly different compared to the mean from 14 HD (33 ±18 and 56 ± 21 versus 10 ± 2.2; p = 0.13 and p = 0.08, respectively). In nine myeloid leukemia patients the marrow-derived P3 level, which was similar to serum P3, was also similar to that in five non-myeloid leukemia patients (23 ± 9.5 versus 27 ± 11.8, p = 0.08). Further P3 was highly expressed on plasma membrane (PM) of both marrow-derived and circulating blasts, whereas NE was only expressed on PM of marrow-derived blasts. Therefore aberrant expression of serine proteases in leukemia may play a role in reversing T cell tolerance by increasing available determinants on MHC-I in leukemia.
Breast Cancer Peptide Epitopes Presented by HLA-A*0201 (48.6)
Authors: Hawkins Oriana E , VanGundy Rodney , Fleshman Annette , Bardet Wilfried , Gonzalez Melva , Wahl Angela , Buchli Rico , Hildebrand William 
Published: January 2023

Abstract
Cellular immune mechanisms detect and destroy cancerous and infected cells via the human leukocyte antigen (HLA) class I molecules that present peptides of intracellular origin on the surface of all nucleated cells. The identification of novel, tumor-specific epitopes is a critical step in the development of TCR mediated immunotherapeutics. In order to directly identify peptide epitopes unique to cancerous cells, secreted human class I HLA molecules were constructed by deletion of the transmembrane and cytoplasmic domain of HLA A*0201. The resulting sHLA-A*0201 was transferred and expressed in breast cancer cell lines MCF-7, MDA-MB-231, and BT-20 as well as in the immortal, non-tumorigenic cell line MCF10A. Stable transfectants producing sHLA-A*0201 were seeded into Bioreactors for production of &gt; 25 mg of sHLA-A*0201. Peptides eluted from affinity purified sHLA were analyzed by mass spectroscopy and peptides derived from proteins with reported cancer association have been identified; BAP31, Cytokeratin 19, KIAA0336, and UGT1 peptide epitopes have been found on cancer cells. The identification of peptides unique to the class I of cancerous breast cells provides putative targets for immune diagnostics and therapeutics.
OH is supported by NSF Graduate Fellowship 2006036207
A Novel Immune-Based Cancer Therapy Using Gene-Silenced Dendritic Cells (48.8)
Authors: Zheng Xiufen , Zhang Xusheng , Vladau Costin , Li Mu , Suzuki Motohiko , Chen Dong , Garcia Bertha , Koropatnick James , Min Wei-Ping 
Published: January 2023

Abstract
Hyporesponsiveness is a major hallmark in dendritic cells (DC)-mediated anticancer immunotherapy. Indoleamine 2, 3-dioxygenase (IDO), an immunosuppressive molecule expressed by DC, is a critical factor mediating hyporesponsiveness to cancer immune therapy. We hypothesized that silencing of IDO in DC using siRNA would enhance anticancer therapy. In this study, DC were cultured in vitro, exposed to melanoma B16 lysate, silenced with IDO siRNA, and injected into C57/BL6 mice. Mice were then challenged with B16 tumor cells. The anticancer effects of IDO-silenced DC therapy, compared with non-silenced, conventional control DC vaccine, were evidenced by
postponed melanoma tumor onset time, anddecreased tumor size.
In addition, after immunization with IDO-silenced DC, the number of CD8+ T cells was significantly increased while CD4+ and CD8+ T cell apoptosis in draining lymph nodes was remarkably reduced. Furthermore, immunization with IDO-silenced DC enhanced tumor antigen-specific T cell proliferation and CTL activity, and decreased numbers of CD4+CD25+FoxP3+ regulatory T cells (Treg). In conclusion, this study is the first to demonstrate a novel anti-tumor vaccine by silencing an immunosuppressive gene (IDO) in DC, which enhanced anti-tumor immunity, reduced T cell apoptosis and Treg cell formation, and prevented tumor growth. IDO-silenced DC have clinical potential as an immune-based therapy.
CCL2 producton in neutrophils (PMN) from peripheral blood of hepatocellular carcinoma patients (49.1)
Authors: Tsuda Yasuhiro , Asai Akira , Fukui Hideo , Tanabe Toshiaki , Teramura Kazuhisa , Fukuda Akira , Hanafusa Toshiaki 
Published: January 2023

Abstract
An immunosuppressive subset of PMN has recently been demonstrated in mice with severe immunocompromised status such as severe systemic inflammatory response syndrome (SIRS), severe thermal injury or severe stress. By CCL2 production, these PMN direct resident macrophages (MƒÓ) to M2MƒÓ. Functional deficiencies of tumor-associated immune cells have been shown in cancer patients bearing acceleration of tumor growth who are known to be immunocompromised hosts. Hepatocellular carcinoma (HCC) was one of a most frequent malignant tumor in worldwide. Repeated episodes of recurrence and metastasis are commonly associated with the poor prognosis of HCC. Therefore, in this study, subsets of PMN from HCC patients were immunobiologically investigated. Thirty HCC patients admitted to Osaka Medical College were randomly enrolled. PMNs were isolated from heparinized peripheral blood using Ficoll-Hypaque and dextran sedimentation. PMNs from 5 healthy donors were used as controls. PMN (1 x 106 cells/ml) were stimulated with 0.0075% SAC for 24 hrs. Culture fluids harvested were assayed for CCL2 by ELISA. After SAC stimulation, CCL2 were produced by all patient PMNs, while none of healthy donor PMNs produced these soluble factors. Moreover, CCL2 production was significantly increased in proportion to tumor size or extent. These results suggest that PMN with a function to produce CCL2 are predominated in HCC patients and they may be involved in their poor prognosis.