bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expansion of Spleen Myeloid Suppressor Cells Represses NK Cell Cytotoxicity in Tumor Bearing Host (49.13)
Authors: Liu Cunren , Yu Shaohua , Zinn Kurt , Wang Jianhua , Grizzle William E , Kappes John , Zhang Huang-Ge 
Published: January 2023

Abstract
Tumor growth promotes the expansion of myeloid suppressor cells. An inverse correlation between natural killer (NK) cell activation and myeloid suppressor cell expansion in tumor-bearing patients and mice prompted us to investigate the role of myeloid suppressor cells in controlling NK cell antitumor cytotocixity. In TS/A breast tumor model, the in vivo NK cell cytotoxicity was impaired in tumor-bearing mice. After adoptive transfer to naive recipients, CD11b+Gr-1+ myeloid suppressor cells freshly isolated from spleens of tumor-bearing mice but not naive mice were able to inhibit NK cell cytotoxicity. An in vivo imaging analysis indicated that the removal of tumors resulted in a significant increase in NK cell cytotoxicity in lung to eliminate injected YAC-1 cells. FACS analysis of the composition of lung leucocytes further indicated that the removal of tumors also lead to the reduction of CD11b+Gr-1+ myeloid suppressor cells accumulated in the lung. These data suggest that CD11b+Gr-1+ myeloid suppressor cells suppress NK cell cytotoxicity. The inhibition of NK cell cytotoxicity is cell-cell contact dependent. Inhibition of perforin but not granzyme B was responsible for myeloid suppressor cell-mediated inhibition of NK cell cytotoxicity. Western blot analyses further suggested that myeloid suppressor cells suppress IL-2 mediated NK cell cytotoxicity by affecting the activity of Stat5.
Tumor exosomes inhibit differentiation of bone marrow dendritic cells (49.14)
Authors: YU Shaohua , Liu cunren , Wang Jianhua , Liu yuelong , Zhang liming , Cong Yingzi , Grizzle william , Zhang huang-Ge 
Published: January 2023

Abstract
The production of exosomes by tumor cells has been implicated in tumor-associated immune suppression. Here we show that, in mice, exosomes produced by TS/A murine mammary tumor cells target CD11b+Gr-1+ myeloid precursors in the bone marrow in vivo and that this is associated with an accumulation of myeloid precursors in the spleen. Moreover, we demonstrate that TS/A exosomes block differentiation of murine myeloid precursor cells into dendritic cells in vitro. Addition of tumor exosomes at day 0 led to a complete block of differentiation into dendritic cells, whereas addition at later time points was less effective. Similarly, exosomes produced by human breast tumor cells inhibited differentiation of human monocytes in vitro. The levels of IL-6 and phosphorylated Stat3 were elevated 12 h after tumor exosome stimulation of murine myeloid precursors, and tumor exosomes were less effective in inhibiting differentiation of bone marrow cells isolated from IL-6 knockout mice. These data suggest that tumor exosome-mediated induction of IL-6 plays a role in blocking bone marrow dendritic cell differentiation.
Downstream effects of decreased microRNA miR-16 levels, found in NZB B cell malignancies, include alterations in cell cycle progression and apoptosis (49.23)
Authors: Salerno Erica , Scaglione Brian , Balan Murugabaskar , Kotenko Sergei V , Coffman Frederick , Raveche Elizabeth 
Published: January 2023

Abstract
Alterations in the 13q14 genomic region containing mir-15a and mir-16-1 have been found in human CLL, resulting in down-regulation of these miRNAs in some patients. NZB mice, serving as a model for CLL, were used to study this particular region on chromosome 14, which shows synteny with the human 13q14 region. We recently identified a point mutation in the 3′flanking region of mir-16-1, similar to the one found in human CLL, that may be associated with decreased levels of miR-16. Decreased miR-16 can result in increased expression of miR-16 target genes, such as bcl-2, leading to failure of tumor cells to undergo apoptosis. When cells from an NZB-derived malignant B cell line are transfected with exogenous miR-16 at various phases of the cell cycle an increase in apoptosis as well as various cell cycle effects can be observed. Cells in or entering S phase remain in S phase longer when treated with miR-16. In summary, alterations in the levels of miR-16 in the NZB model, resulting from mutations in the 3′flanking region, may be associated with changes in cell cycle transit and apoptosis induction. These findings suggest that miR-16 plays a role in the development and progression of B cell malignancies.
Vitamin C potentiates gefitinib-mediated tumor cell growth inhibition in human lung cancer cells (49.26)
Authors: Bae Seyeon , Hahm Eunsil , Lee Kyung Eun , Kang Jae Seung , Jung Da Jung , Kim Jee Eun , Lee Seung Koo , Hwang Young Il , Shin Dong Hoon , Lee Wang Jae 
Published: January 2023

Abstract
Malignancies of lung are the leading causes of cancer mortality in world wide and there are so many limitations in early detection of lung cancer, which eventually made the cancer detected at advanced stage. Conventional cytotoxic drugs have showed more increased response rate with grave toxicities. Recently, successful therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in lung cancer patients have been reported, although a mono-therapy still showed low response rate. Here, we investigated to elucidate whether the vitamin C has the adjuvant role as an antioxidant or other functions in EGFR tyrosine kinase inhibitor, gefitinib (Iressa ¢â), therapy in lung cancers. We used three kinds of human non-small cell lung cancer cell (NSCLC) lines depending on EGFR mutation, A549, Calu-3 and HCC827. A549 and Calu-3 are NSCLC cell lines which have wild type EGFR domain and showed relative resistance to gefitinib treatment. HCC827 is well known cell line of EGFR domain mutation. Vitamin C showed reduction of S phase in cell cycle and had function as an anti-oxidant. Also that could induce synergistic effects of EGFR tyrosine kinase inhibitor therapy in cellular proliferation and down-regulation of EGFR phosphorylation, AKT & ERK activation. Synergistic inhibitory effects of vitamin C with EGFR tyrosine kinase inhibitor therapy are showed in both wild and mutant EGFR cell lines. In this present study, we demonstrated an possible adjuvant role of vitamin C in EGFR tyrosine kinase inhibitor therapy in human NSCLC.
Expression of Vascular Endothelial Growth Factor Receptor 1(VEGFR-1), but not VEGFR-2 in Activated T Lymphocytes and Its Function in Response to VEGF (49.28)
Authors: Shin Jin Young , Kim Jung Sik , Kim Bongi , Yun Il Hee , Park Chung Gyu 
Published: January 2023

Abstract
Vascular endothelial growth factor (VEGF) is the most potent proangiogenic mediator that plays an important role in tumor growth and progression. Recent evidence suggests an alternate role of VEGF and its receptor 1 and 2 (Flt-1 and Flk-1) on host immune response to tumors. Activated or effector T lymphocytes are the chief type of defense cells mediating cellular immunity against tumor cells. However, expression of VEGF receptors in activated T lymphocytes is not yet identified and its function is unclear. We have studied expression of VEGF receptors, VEGFR-1 and VEGFR-2 in these cells. Activated T lymphocytes express mRNA for VEGFR-1 and R-2. But these cells are found to express the protein for VEGFR-1, which is one of the receptors for VEGF. We demonstrate that treatment with VEGF directly induced the production of IL-10 with slight reduction of IFN-γ although it dose not affect T cell proliferation. A chemotaxis assay reveals that activated T lymphocytes have the ability to migrate in response to VEGF. Our data suggest that in the presence of VEGF, VEGFR1 positive-activated T lymphocytes may migrate to tumor sites and be involved in tumor tolerance through IL-10
Expression and functions of Xg protein on Ewing’s sarcoma cells (49.29)
Authors: Meynet Ophelie , Marti Virginie , Scotlandi Katia , Bernard Alain , Bernard Ghislaine 
Published: January 2023

Abstract
The human Xg molecule is a 26 kD transmembrane glycoprotein normally displayed by red cells only. It shows 48 % of homology with CD99, known as a regulator of cellular adhesion and migration. Xg is encoded by the PBDX gene located on the pseudoautosomal region of X chromosome. To determine the functional role of Xg we have developed a Jurkat T cell model transfected with the Xg cDNA. Xg positive Jurkat T cells spontaneously display a strongly activated cytoskeleton with extensive actin polymerization, microvilli formation and strong aggregation. Moreover, this was accompanied by an increase migratory ability upon SDF-1 chemoattraction.
Unexpectedly, we found Xg to be expressed by malignant cells and particularly by 80% of Ewing sarcomas cell lines. We have transfected the Xg cDNA in Xg negative Ewing’s sarcoma cell line BRZ which induced similar activities as those we found for transfected Jurkat T cells. It must be now looked whether Xg expression like CD99 expression is restricted to ES cells among sarcoma cells is linked to an invasive phenotype.
Inhibition of Bence-Jones protein synthesis by RNA interference (49.30)
Authors: Phipps Jonathan Earl , Foster James Stephen , Kestler Daniel , Alan Solomon , Wall Jonathan Stuart 
Published: January 2023

Abstract
A main contributing factor to the morbidity and mortality of patients with multiple myeloma results from the pathologic deposition as casts within renal tubules of monoclonal Ig light chains, i.e., Bence-Jones proteins (BJP). As an alternative to plasma cell chemotherapy to reduce BJP synthesis and thus prevent myeloma (cast) nephropathy we have investigated another means to achieve this objective, namely, RNA interference (RNAi). Experimentally, we have stably transfected the SP2/O mouse myeloma cells with a construct containing the V, J, and C region of a λ BJP (Wil) under the control of a CMV promoter and have shown that they constitutively express measurable quantities of mRNA and protein Wil. Treatment of these cells with synthetic, small double stranded RNA based on the Wil protein sequence reduced target mRNA levels by 2-fold at 48 h and protein production by 30% at 72 h, as compared with controls. These data provide conclusive evidence that RNAi can effectively reduce BJP production in vitro and provide the base for testing the clinical potential of this strategy using a relevant in vivo murine model of myeloma (cast) nephropathy.
Pre-operative interleukin-6 production by mononuclear blood cells predicts survival after radical surgery for colorectal carcinoma (49.31)
Authors: Clinchy Birgitta , Fransson Annelie , Druvefors Bengt , Hellsten Anna , Håkansson Annika , Gustafsson Bertil , Sjödahl Rune , Håkansson Leif 
Published: January 2023

Abstract
Colorectal cancer (CRC) is one of the most common forms of cancer in the Western world with an estimated yearly incidence rate of 77 per 100 000 in North America. Besides histopathological staging, there is a great need for tests giving more accurate prognostic information defining the patient population in need of closer follow-up and/or adjuvant therapy. Elevated serum levels of IL-6 have been found in patients with CRC. The source of the serum IL-6 is still unclear.
Peripheral blood mononuclear cells (PBMC) were isolated preoperatively (within a week before surgery) from 34 patients undergoing radical surgery for colorectal cancer. The PBMCs were cultured for 24 hours in the presence of autologous serum and LPS. IL-6 production was measured with ELISA. Staging based on histopathology was performed in all patients.
A production of &gt;5000 pg/ml of IL-6 identified CRC patients with a poor prognosis. Eight out of thirteen patients with &gt;5000 pg/ml IL-6 died from cancer within the follow-up period (at least 54 months) whereas no cancer related deaths were recorded among twenty-one patient with 5000 pg/ml IL-6 or less. IL-6 production was identified as an independent prognostic factor. These data support the hypothesis that the adaptive immune system is of importance for tumour progression and that immunological parameters can serve as useful as prognostic and predictive tools in cancer management.
Tumor modulation of T-helper cytokine secretion (49.6)
Authors: Lathers Deanne M.R. , Kearney Patricia L. , Gibbs Kiki , Young M. Rita 
Published: January 2023

Abstract
Tumor modulation of T-cells contributes to tumor-induced immune suppression. To determine if tumor-derived factors selectively recruit T-cell subpopulations, the migration of T-cells in response to SCC VII/SF or epithelial cell (epi)-conditioned media (CM) was determined by Transwell chemotaxis assay. Increased levels of CD4+CD25+ cells were observed in T-cells migrating in response to SCC-CM. Following stimulation, T-cells migrating in response to SCC-CM had diminished IFN-γ secretion as compared to epi-CM. Additional studies determined whether SCC-CM actively suppresses IFN-γ secretion by Th1 cells in the tumor microenvironment. Th1 and Th2 cells were differentiated from naïve lymph node cells then cultured with SCC or epi-CM. After overnight stimulation, IFN-γ and IL-10 secretion was assessed by ELISA. Following SCC-CM treatment, IFN-γ secretion by Th1 cells was diminished as compared to epi-CM treatment. IL-10 secretion by Th2 cells treated with either CM was unaffected. The effects of SCC-CM on IFN-inducible chemokines are currently under investigation. These results identify mechanisms of tumor-induced immune suppression by demonstrating that Th2 cells are selectively recruited in response to SCC-derived factors and that Th1 cells in the tumor microenvironment have suppressed IFN-γ secretion.
Supported by Dept. of Veterans Affairs, American Cancer Society and National Cancer Institute.
The role of paracrine IL-6 and IL-10 in neuroblastoma progression (49.9)
Authors: Song Liping , Ara Tasnim , Salo Jill , Deng Zhong-bin , Asgharzadeh Shahab , Ji Lingyun , Sposto Richard , DeClerck Yves A , Seeger Robert C , Metelitsa Leonid S 
Published: January 2023

Abstract
Tumor-associated inflammation may play a critical role in tumor progression but its mechanism is yet poorly understood. We have detected elevated levels of IL-6 (2.9 – 88.9 pg/ml) in serum from 10 patients with recurrent stage 4 neuroblastoma. Although none of 5 tested neuroblastoma cell lines produced either IL-6 or IL-10, their conditioned medium selectively induced both cytokines in short-term culture of normal PBMC in a time- and dose-dependent manner as determined by 9-plex Luminex® assay. Treatment with rhIL-6 enhanced neuroblastoma cell proliferation as measured by BrdU incorporation and was sufficient for their survival in a serum-free medium. IL-6 induced rapid STAT3 phosphorylation in neuroblastoma cells and production of yet unidentified soluble factors that inhibited dendritic cell maturation. Gene expression analysis with TaqMan® Low Density Arrays of primary metastatic tumors from 40 patients revealed that elevated expression of IL-6 or IL-10 was associated with a poor 5-year event-free survival: 35% +/−11% vs. 75 +/−10% when IL-6 or IL-10 expression was above and below median levels, respectively (P &lt; 0.02). Thus, although neuroblastoma cells do not express IL-6 and IL-10, they can induce expression of these cytokines by inflammatory cells. These cytokines can then have a paracrine effect on tumor cells and other elements of tumor microenvironment that may promote tumor progression.
Murine L5178Y T-cell lymphoma cells prime macrophages via CD40-CD40L interaction to mediate LPS-activated antitumor effects in vitro (50.13)
Authors: Buhtoiarov Ilia N. , Rakhmilevich Alexander L. , Sondel Paul M. 
Published: January 2023

Abstract
We present that L5178Y murine T-cell lymphoma cells can prime naïve murine macrophages (Mϕ) to subsequent LPS stimulation, resulting in antitumor effects in vitro against L5178Y cells. Priming occurred in both cell-type and TLR specific manner, as L5178Y tumor cells (TC), but not naïve splenocytes, primed Mϕ to ligation of TLR4 but not TLR9. L5178Y-primed Mϕ also showed down-regulation of CD40 and CD86 and up-regulation of B7H1, with no changes of TLR4, B7H4, NKG2D and MHC-II expression. Among different TC lines, the priming effect was limited to murine TC of T cell (L5178Y and YAC-1) but not B cell (A20) or nonmyeloid (B16) origin. Human TC lines including Jurkat (T cell), Daudi (B cell), and M21 (melanoma) failed to substantially prime Mϕ. Neither L5178Y-conditioned supernatants nor co-culture of Mϕ and L5178Y TC in transwells resulted in priming, indicating that direct L5178Y TC-Mϕ contact was needed. Furthermore, TLR4-ligation must not precede contact with L5178Y TC in order to induce tumoritoxic Mϕ. Among several receptor-ligand pairs reciprocally expressed on Mϕ and L5178Y TC and potentially involved in the Mϕ priming, CD40 (expressed on Mϕ) and CD40L (expressed on L5178Y TC) appeared to play the most important role, as blocking their interaction with anti-CD40L mAb substantially reduced in vitro tumoritoxicity. Hence, contact with TC may facilitate Mϕ-mediated immune surveillance against certain cancers.
Anti-B7-1/B7-2 mAb treatment enhanced anti-tumor immunity in TRAMP mice (50.14)
Authors: Zheng Pan , Zhou Penghui , Zheng Xincheng , Zhang Huiming , Liu Yang 
Published: January 2023

Abstract
Immune tolerance is the major mechanism applied by the immune system to discriminate between self and non-self. There is sufficient evidence to show that CD4+CD25+ Treg cells play an important role in the maintenance of peripheral tolerance. Accumulating evidence suggests that CD4+CD25+ Treg cells also suppress tumor antigen-specific immunity in tumor-bearing mice and in humans. Therefore, breaking Treg-mediated peripheral tolerance to tumor antigens may enhance anti-tumor immunity. B7:CD28 interactions are needed for both the development and maintenance of CD4+CD25+ Treg cells. This raises the possibility that blocking the B7 signal may break tumor tolerance by reducing the number of CD4+CD25+ Treg cells. Here we show that administration of anti B7-1/B7-2 mAbs either at a beginning stage or at an intermediate stage of prostate cancer development significantly enhanced anti-tumor immunity by postponing the disease process. Anti-tumor immunity was improved after inhibiting the generation of CD4+CD25+ regulatory T cells in thymus and periphery without a hint of autoimmune disease. Our results demonstrate that blocking the costimulatory pathway with anti B7-1/B7-2 antibodies can enhance anti-tumor immunity.
Type II NKT cells suppress tumor immunosurveillance enhanced by type I NKT cells (50.16)
Authors: Terabe Masaki , Ambrosino Elena , Takaku Shun , Peng Judy , Miyake Sachiko , Halder Ramesh , Yamamura Takashi , Kumar Vipin , Berzofsky Jay 
Published: January 2023

Abstract
NKT cells are a T cell subset that recognizes glycolipid antigens presented by CD1d. They consist of 2 subsets: the widely studied type I expressing a canonical TCR, Vα14Jα18, and a little known type II of non-Vα14Jα18 NKT cells. Here, we examined the role of type I and II NKT cells in the regulation of tumor immunosurveillance. Jα18 KO mice, which lack type I but retain type II NKT cells, had a significantly larger tumor burden of CT26 tumor injected i.v. than wild-type mice early in tumor growth. This result suggested that the absence of type I NKT cells allows type II NKT cells to further suppress tumor immunosurveillance compared to wild-type mice that have both types of NKT cells. The role of NKT cell subsets was examined by stimulating them with antigens that specifically activate either type I or type II NKT cells. Mice treated with type I NKT cell agonist α-galactosylceramide or the weaker agonist OCH almost completely rejected tumor. In contrast, mice treated with a single dose of type II NKT cell-stimulating sulfatide had significantly increased tumor burden. Simultaneous stimulation of both types of NKT cells in vivo significantly suppressed the protective effect of type I NKT cell stimulation. Overall, the results suggested that stimulation of type I NKT cells promotes tumor immunosurveillance, whereas stimulation of type II NKT cells suppresses, and that type II NKT cells suppress type I NKT cell activity.
Targeting molecular and cellular inhibitory mechanisms for improvement in anti-tumor memory responses reactivated by tumor cell vaccine (50.17)
Authors: Dong Haidong 
Published: January 2023

Abstract
Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor antigens via re-stimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms which function to limit the recall responses of tumor-specific immunity exist remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes. We demonstrate that although a whole cell irradiated tumor cell vaccine can trigger a functional anti-tumor memory response in the bone marrows of mice with established tumors, these responses do not culminate in the regression of established tumors. In addition, a CD103+ regulatory T (Treg) cell subset accumulates within the draining lymph nodes of tumor-bearing mice. We also show that B7-H1 (CD274, PD-L1), a negative costimulatory ligand, and CD4+ Treg cells collaborate to impair the recall responses of tumor-specific memory T cells. Specifically, mice bearing large established RENCA tumors were treated with tumor cell vaccination in combination with B7-H1 blockade and CD4+ T cell depletion (triple therapy treatment) and monitored for tumor growth and survivability. Triple treatment therapy induced complete regression of large established RENCA tumors and raised long-lasting protective immunity. These results have implications for developing clinical antitumoral vaccination regimens in the setting where tumors express elevated levels of B7-H1 in the presence of abundant Treg cells.
Assessment of CCL5 transfected murine mammary adenocarcinoma cells for alterations in disease progression (50.2)
Authors: Kurt Robert A , Jayasinghe Mevan , Nair Priyanka , O’Donnell Cara , Werner Michael 
Published: January 2023

Abstract
A previous study showed that reducing tumor-derived CCL5 expression using RNA interference did not significantly influence growth rate or metastatic ability of the 4T1 tumor. Since 4T1 is an aggressive tumor that constitutively expresses CCL5 and exhibits low immunogenicity we wanted to determine whether tumor derived CCL5 expression could influence disease progression of a less aggressive and non-metastatic tumor. For this purpose we used the 168 tumor which does not constitutively express CCL5. We cloned the full length CCL5 gene, inserted it into a eukaryotic expression vector and transfected the 168 tumor. Whereas the parental and vector transfected control 168 tumors expressed 0–30pg/ml of CCL5, transfection with the CCL5 expression vector resulted in up to 1000pg/ml of CCL5. To determine whether CCL5 expression would influence growth or metastasis of the 168 tumor we generated clones of the CCL5 transfected tumor. After 4 weeks of in vitro passaging, in the absence of G418, CCL5 expression remained elevated indicating the generation of stable lines. Analysis of tumor growth rates revealed that tumor-derived CCL5 expression alone was not sufficient to modulate growth of the 168 tumor. These clones are being used to determine whether CCL5 transgene expression is sufficient to modulate metastatic ability of the tumor.
This work was supported by the National Institutes of Health R15 CA111539-01.