bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-17 promotes inflammation associated tumor development (100.14)
Authors: Xu Hui , He Donggou , Li Hui , Yusuf Nabiha , Elmets Craig , Athar Mohammad , Katiyar Santosh , Mountz John 
Published: January 2023

Abstract
The mechanism for inflammation associated tumor development is a central issue for tumor biology and immunology. IL-17 is an important cytokine for inflammatory and autoimmune diseases. Although IL-17 producing cells are detected in cancer patients and tumor bearing mice, the role of IL-17 mediated inflammation in tumor development remains to be determined. In the current studies, we showed that IL-17 receptor-A gene deficient mice (IL-17R-/-) were resistant to chemical induced carcinogenesis in the skin. Moreover, the defect in IL-17R reversed the increased susceptibility of IL-12p35 deficient mice to tumor development. Analysis showed that angiogenesis and infiltration of myeloid cells were inhibited whereas the infiltration of CD8 T cells was increased in the inflamed skin of IL-17R-/- mice. The development of myeloid derived suppressor cells was inhibited in IL-17R-/- mice. Inflammation induced Cox-2 activity and S100A8/A9 proteins were inhibited and inflammation associated epidermal hyperplasia were suppressed in IL-17R-/- mice. Furthermore, the production of tumor promoting inflammatory cytokines IL-1β and TNF-α were reduced. These findings demonstrate that IL-17 signals are required for inflammation associated tumor development. The study provides insights into a novel mechanism by which IL-17 mediates tumor promoting inflammation and induces tumor escape from immune surveillance. It has major implications for targeting IL-17 in prevention and treatment of tumors.
Do stress response genes play a role in maintaining MDSC survival and suppression? (100.17)
Authors: Beury Daniel , Fitzgerald Phillip , Srivastava Minu , Ostrand-Rosenberg Suzanne 
Published: January 2023

Abstract
Myeloid- derived suppressor cells (MDSC) contribute to immune suppression in tumor bearing individuals. Their suppression and survival are increased by inflammation. MDSC production of toxic radicals is the primary mechanism of suppression but the toxic mediators do not affect the MDSC themselves. We are investigating stress response genes that may maintain MDSC survival and facilitate suppression. BALB/c mice were injected with BALB/c derived mammary carcinoma 4T1 or 4T1 constitutively expressing the pro-inflammatory cytokine IL-1β (4T1/IL-1β). Primary tumors were surgically removed after 25 days. At 35 days, spleens were harvested and assayed for the percentage of Gr1+ CD11b+ MDSC. Surgical removal of 4T1 results in a regression of the MDSC population, however MDSC do not regress in mice bearing 4T1/IL-1β tumors, confirming that inflammation increases MDSC survival. Western blots and confocal microscopy of MDSC induced by 4T1 and 4T1/IL-1β tumors localize Nrf2 in the nucleus, demonstrating that Nrf2 is activated in MDSC. Catalase, a protein transcriptionally regulated by Nrf2, when added to a T cell activation assay eliminates MDSC suppressive activity. Addition of catalase to T cells co-cultured with MDSC and peptide causes a synergistic effect, activating T cells to a greater level than peptide alone. Collectively these data suggest that stress genes may play a role in maintaining MDSC survival and suppressive activity.
CD28 costimulates macrophage suppression via increased IFNg production (100.21)
Authors: Riggs James , Kozlowski Megan , Composto Gabriella , Silberman Dan 
Published: January 2023

Abstract
The high macrophage to T cell ratio (Mf:T) characteristic of the tumor microenvironment can be modeled using peritoneal cavity (PerC) cell culture. C57BL/6J PerC Mfs suppress T cell activation by IFNg-triggered expression of iNOS and IDO, enzymes that consume Arg and Trp. Attempts to reverse suppression by CD28 costimulation actually increased suppression and ELISPOT analyses revealed this was due to increased numbers of IFNg-secreting cells (gSC). Comparative analyses showed that C57BL/6 mice had more gSC than B-1 B cell deficient, BALB.xid mice and that these strains both had more gSC than BALB/c mice even though the latter had the greatest increase in gSC following costimulation. Titration experiments revealed that increased PerC cell density reduced the need for costimulation and increased gSC number. Both CD80 and CD86 knockout (KO) mice had fewer gSC than wildtype mice with CD80 KOs having fewer than CD86 KOs. These data reveal a “braking” role for IFNg in T cell responses and suggest that, rather than promote T cell activation, CD28-mediated costimulation could foster suppression of cell-mediated immunity via increased formation of Mf-T cell synapses within tumor microenvironments. Supported by NIH AREA R15- CA136901-01.
Mouse strain differences in macrophage regulation of peritoneal T cells (100.22)
Authors: Riggs James , Composto Gabriella , Bartlett Thomas , Chaviano Gabriella , Gonzalez Diana 
Published: January 2023

Abstract
Murine peritoneal cavity (PerC) T cells from C57BL/6J mice respond poorly to CD3 ligation due to the high concentration of macrophages (mf) found in this anatomic location. Mfs suppressed T cell activation by their catabolism of ARG by iNOS. To further investigate PerC mf-T cell interaction, we characterized the immunobiology of these cells from C57BL/6J, BALB/c, BALB.xid, and DBA/2J mice. C57BL/6J mice had the greatest number of PerC T cells and the lowest CD4:CD8 ratio. Comprehensive FACS analysis revealed an increased frequency of activated (CD44hi, CD62lo, CD45Rblo, GITRhi) T cells in the PerC relative to conventional lymphoid (lymph node, spleen) tissue. Although there were significant numbers of CD25+, GITR+ T cells in the PerC, Foxp3+ Treg cells were not enriched relative to LN or SP cells. The degree of suppression of T cell activation varied among the strains as well as the mechanism involved. Immunosuppressive prostaglandin production was a modest factor in all strains. Suppression best correlated with the number of IFNg-secreting cells: PerC cells from the “Th1 strain” C57BL/6J and the “Th2 strain” BALB/c were the most and least suppressed, respectively. These results reveal strain-specific differences in PerC mf suppression of T cells. Supported by NIH AREA R15-CA136901-01.
Cancer cells utilize a novel regulatory subset of B cells to promote escape and metastasis (100.26)
Authors: Olkhanud Purevdorj , Damdinsuren Bazarragchaa , Sen Ranjan , Gress Ronald , Biragyn Arya 
Published: January 2023

Abstract
B cells play an important role in antigen presentation and antibody production. However, they appear to exhibit suppressive function inhibiting autoimmune responses in mice. Yet, it remains unknown whether regulatory B cells exist or participate in cancer progression. Here, we demonstrate that a unique B cel subset is induced from resting B cells by cancer cells. These B cells, designated as tumor Bregs (tBregs), are poorly proliferative and express high level of IL-2Rα. The major function of tBregs is to suppress T cell responses, as they efficiently and in dose dependent manner inhibits a proliferation of T cells stimulated with anti-CD3/28 beads. The suppressive activity of tBregs is a cell contact-dependent, but Fas/FasL- and PD1/B7H1-independent, and unlike any other reported regulatory cells, does not require soluble factors such as IL-2, IL-10, TGFβ, IL-27 and IL-35. Importantly, we show for the first time, tBregs induce a conversion of Tregs from non-regulatory CD4+ T cells. Taken together, tBregs are an important and distinct subset of regulatory cells which promote cancer escape and metastasis through direct and indirect (via Tregs) suppression of cellular responses. This work was supported by the Intramural Research Program of the National Institute on Aging, NIH.
Advanced liver disease due to hepatitis C infection is associated with reduced CD19+CD27+ memory B-cells (100.29)
Authors: Kaplan David , Iyer Tara , Carpenter Erica , Vonderheide Robert 
Published: January 2023

Abstract
Advanced neoplasia is associated with defects in B-cell memory. Hepatocellular carcinoma (HCC) frequently arises in the setting of hepatitis C-induced cirrhosis. We hypothesized that memory B-cells from patients with HCC would be reduced in frequency relative to non-cancer bearing cirrhotics and non-cirrhotic HCV. We studied PBMC samples from HCC+ HCV+ cirrhotic patients (n=12), HCC- HCV+ cirrhotic patients (n=12), HCC- HCV+ non-cirrhotic patients (n=10), and HCV- normal donors (n=10) for surface expression of CD19, CD21, CD27, and FcRL4. The frequency of CD27+ memory cells among CD19+ B-cells was significantly lower in patients with cirrhosis (± HCC) compared to HCV+ non-cirrhotic patients (mean ± SE, 16.0 ± 2.7 vs. 29.7 ± 3.8%, p = 0.007) and normal donors (p=0.034). The frequency of atypical memory B-cells (CD27-CD21-/CD19+) was significantly greater among HCC+ patients (31.1 ± 3.7%) compared to HCC- cirrhotics (19.0 ± 3.5%, p=0.023), non-cirrhotic HCV+ patients (16.4 ± 3.9%, p=0.009) and normal donors (17.3 ± 3.9%, p=0.014). Among HCC patients, there was a positive correlation between CD27-CD21- B-cell frequency and AFP levels (R2 = 0.55, p=0.04). Conclusions: HCV-induced cirrhosis is associated with loss of CD19+CD27+CD21+ memory B-cells, while HCC is associated with an increase in CD19+CD27-CD21- atypical memory B cells. These findings identify a phenotype that may be associated with immunodeficiency in cirrhosis as well as with tumor-induced immune suppression in HCC.
Tumor-derived mesenchymal stem cells enhance tumor development via nitric oxide (100.33)
Authors: Ren Guangwen , Zhang Liying , Wen Ting , Zhao Xin , Yuan Zeng-rong , Zhang Jimin , Ling Weifang , L'huillie Andrew , Shao Changshun , Shi Yufang 
Published: January 2023

Abstract
Mesenchymal stem cells (MSCs) have been widely applied in treating immune disorders due to their immunosuppressive capacity. However, a major concern for the clinical application of MSCs is their risk to promote tumorigenesis. In the meantime, there are increasing reports about the identification of MSCs from various tumor tissues. In this study, we compared the tumor-derived MSCs with bone marrow-derived MSCs (BM-MSCs) in vitro and in vivo. We found that only tumor-derived MSCs, but not BM-MSCs enhance tumor development. In vitro, tumor-derived MSCs had a similar capacity to suppress T cell receptor-induced T cell proliferation via nitric oxide (NO), but exhibited a more vigorous inhibition on the differentiation and maturation of dendritic cells, compared to BM-MSCs. Moreover, co-culture with tumor-derived MSCs led bone marrow cells to differentiate into more CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs), another NO-producing immunosuppressive cell population. In vivo, more MDSCs were also detected after administration of tumor-derived MSCs, but not BM-MSCs in tumor-bearing mice. Furthermore, tumor-derived MSCs, but not BM-MSCs significantly enhanced tumor growth, which was partially dependent on NO. Therefore, NO-dependent tumor promoting effect is likely not mediated by MSCs themselves, but through the indirect action of MDSCs. Our findings indicate a novel role of MSCs in tumor progression and provide new information for the clinical application of MSCs.
Response Gene to Complement 32 regulates chromatin assembly in colon cancer (100.35)
Authors: Tegla Cosmin , Vlaicu Sonia , Cudrici Cornelia , Fosbrink Matthew , Nguyen Vingh , Azimzadeh Philippe , Rus Violeta , Shamsuddin Abulkalam , Rus Horea 
Published: January 2023

Abstract
Response Gene to Complement 32 (RGC-32) is induced by complement activation and plays an important role in cell cycle activation. In this study we investigated the role of RGC-32 in colon cancer cell cycle. Our data indicate that RGC-32 expression is significantly higher in adenomas than in normal colon tissue. The expression of RGC-32 was higher in advanced stages than in precancerous states or the initial stages of colon cancer. In addition C5b-9 neoantigens deposits were found to be present on the colon tumor cells expressing RGC-32. In order to identify the genes that are regulated by RGC-32, we used gene array to investigate the effect of RGC-32 knockdown on gene expression in the SW480 cell line. Of the 230 genes that were differentially modulated by RGC-32, a group of genes involved in chromatin assembly were the most significantly regulated. RGC-32 knockdown induced an increase in acetylation of histones H2B lysine 5 (H2BK5), H2BK15, H3K9, H3K18, and H4K8, a decreased expression of SIRT1 and trimethylation of histone H3K27. In addition, RGC-32 knockdown caused a significantly higher percentage of SW480 cells to enter S phase, and subsequently G2/M. These results strongly suggest that silencing of the RGC-32 is associated with chromatin remodeling and activation of cell cycle. Since RGC-32 is induced by C5b-9 is possible that activation of complement has a benefic effect in colon cancer by inducing the expression of this tumor suppressor gene.
Tumor-secreted PGE2 inhibits CCL5 production from activated macrophages through cAMP signaling pathway (100.6)
Authors: Liu Jianguo , Qian Xuesong 
Published: January 2023

Abstract
It is well known that tumor cells could evade immuosurveillance by dampening host immune responses and shaping host stromal cells to favor its growth. CCL5 has been shown to play important roles in T cell proliferation, IFN-g and IL-2 production, which promotes differentiation and proliferation of Th1 cells important for immune defense against intracellular infection. Here we report that the CCL5 mRNA expression and protein production were significantly reduced in tumor-bearing mice compared with tumor-free mice during endotoxic shock. Our data further demonstrate that soluble factors secreted from tumor cells inhibited CCL5 mRNA expression and protein production in LPS-stimulated macrophages. The inhibition of CCL5 expression was regulated at the level of post-transcription. NS398, a selective inhibitor of enzymatic activity of cyclooxygenase 2 in PGE2 synthesis, could reverse the inhibitory effect of tumor cells on LPS-induced CCL5 expression. Moreover, PGE2 and cAMP analog Forskolin could mimic the inhibitory effect of tumor cells on CCL5 expression and blockade of cAMP signaling by H89 completely reversed the inhibitory effect. Taken together, our data indicate that PGE2 secreted from tumor cells suppresses CCL5 expression in LPS-activated macrophages through a cAMP signaling pathway, which may result in suppression of host immune responses against subsequently bacterial infection.
In vitro enhancing oxidative phosphorylation by rapamycin in proliferative CD8+ T cells during antigenic priming augments the generation of long-lived memory T cells in vivo (101.11)
Authors: He Shan , Kato Koji , Jiang Jiu , Wahl Daniel , Mineishi Shin , Cui Shuaiying , Glick Gary , Murasko Donna , Zhang Yi 
Published: January 2023

Abstract
Oxidative phosphorylation is critical to the transition of effectors to memory T cells. However, whether increasing oxidative phosphorylation in proliferative CD8+ T cells during antigenic priming can augment memory T cell generation remains unknown. Using T cell receptor transgenic CD8+ T cells, we found that rapamycin significantly increased the oxidative phosphorylation in antigen-primed naïve CD8+ T cells in vitro without inhibiting their activation and proliferation. Augmented oxidative phosphorylation endowed the rapamycin-treated T cells great ability to survive after IL-2 withdrawal, whereas all the untreated control cells rapidly diminished. Rapamycin-treated CD8+ T cells expressed high levels of CD62L and CD127 but low levels of KLRG-1, PD-1 and IFN-γ. When adoptively transferred in vivo, CD8+ T cells derived from rapamycin-treated cultures generated 5-fold more memory T cells over a period of 6 months than control cells. These long-lived memory T cells had potent ability to produce IFN-γ and proliferate when reexposed to the specific antigen both in vivo and in vitro. These data indicate that augmentation of oxidative phosphorylation in T cells by rapamycin in vitro during antigenic priming dramatically increases both the number and quality of memory precursors, thereby enhancing the generation of long-lived memory T cells. Our findings may have significant implications in optimizing T cell properties to improve the efficacy of adoptive immunotherapy.
Many chronic lymphocytic leukemia antibodies bind apoptotic cells with exposed non-muscle myosin heavy chain IIA in a similar manner as natural antibodies (101.13)
Authors: Chu Charles , Catera Rosa , Zhang Lu , Didier Sebastien , Agagnina Briana , Kaufman Matthew , Kolitz Jonathan , Allen Steven , Rai Kanti , Chiorazzi Nicholas 
Published: January 2023

Abstract
Chronic lymphocytic leukemia (CLL) mAbs containing an IGHV1-69, IGHD3-16 and IGHJ3 rearrangement with a nearly identical or stereotyped sequence (subset 6) recognize non-muscle myosin heavy chain IIA (MYHIIA). Immunohistochemistry showed that MYHIIA becomes exposed on the surface of apoptotic cells. Flow cytometry with 7-amino-actinomycin D and Annexin V-Phycoerytherin showed that MYHIIA exposure (and concomitant subset 6 CLL mAb binding) occurs in a subgroup of both early and late apoptotic cells. Because other CLL mAbs bind apoptotic cells, the binding of MYHIIA exposed apoptotic cells (MEACs) to a panel of CLL mAbs, only two from subset 6, was measured by flow cytometry. Most CLL mAbs (16/26) bound MEACs well. The MEAC binding level inversely correlated with the degree of IGHV mutation. CLL patients with unmutated IGHV (≤ 2%) tend to have shorter survival times. Similarly, CLL mAbs with high binding to MEACs correlated with shorter patient survival. Natural antibodies are characterized by unmutated IGHV and binding to apoptotic cells. Thus, binding of normal serum antibodies to MEACs was tested. Serum samples had reactivities comparable to CLL mAbs with high binding to MEACs, whereas an antigen-selected human antibody specific for CD20 had little MEAC reactivity. Thus, many CLL leukemic clones may derive from natural antibody-expressing B cells, such as B-1 cells, and stimulation by MEACs could lead to development and/or expansion of CLL leading to poor patient outcome.
Interleukin-18 regulates transferrin-induced cell proliferation in MCF-7, breast cancer cell line. (101.14)
Authors: Park Sunyoung , Cho Dae-Ho 
Published: January 2023

Abstract
Interleukin-18 (IL-18) has been reported to enhance cell growth and proliferation in cancer. Transferrin is an iron carrier protein that is responsible for cell growth in both normal and highly proliferative cells like cancers. Although increased serum levels of IL-18 and transferrin in cancer patients correlate with malignancy, little is known about the role of IL-18 and transferrin in the cellular response. Here, we found that exogenous transferrin induces cell growth in human breast cancer cell line, MCF-7. The proliferation rate of MCF-7 cells was reduced when endogenous transferrin expression was inhibited by trasferrin-siRNA transfection. Additionally, we discovered that the expression of endogenous transferrin lies under the control of IL-18 via the MAPK pathway. In conclusion, our data indicate that IL-18 has a pro-cancer effect of accelerating cell proliferation rate by increasing production of endogenous transferrin through the MAPK pathway. Thus, we suggest IL-18 as an inducer of endogenous transferrin expression in breast cancer.
Detection of RET/PTC-associated class I and II-restricted phosphopeptides as tumor specific antigens. (101.25)
Authors: Wixted Josephine , Eisenlohr Laurence 
Published: January 2023

Abstract
Cancer immunotherapy continues to be a viable potential therapy for many tumor types, however, discovering the existence of and breaking tolerance to tumor specific antigens remains a challenge. In our strategy we will take advantage of a common theme of all cancer cell types - the constitutive activation of signal transduction members that promote cell survival and proliferation. Post-translational modification of tyrosine, serine, and threonine via the addition of a phosphate group can both activate signal transduction pathways and generate the production of “neophosphoantigens”. Here we use both sodium vanadate and a model fusion oncogene, RET/PTC, to transform fibroblasts and examine the immunoreactivity of phosphoantigens derived from class I and class II.
T-bet and Eomesodermin are required for adaptive immunity against cancer (101.27)
Authors: Zhu Yibei , Ju Songguang , Chen Elizabeth , Dai Shao , Li Changyou , Liu Lin , Zhang Xueguang , Lu Binfeng 
Published: January 2023

Abstract
Cell-mediated adaptive immunity is very important in tumor immune surveillance and tumor vaccination. However, the genetic program underlying an effective adaptive anti-tumor immunity is elusive. T-bet and Eomes have been suggested to be master regulators of Th1 cells and CD8+ T cells. Whether they are important for anti-tumor immunity is controversial. Here we show that lack of T-bet and Eomes has resulted in profound defects in adaptive anti-tumor immune responses in both prophylactic and therapeutic settings. T-bet and Eomes are also important for CD8+ T cell activation without affecting T cell clonal expansion, the gaining of effector phenotype and cytolytic function. Unexpectedly, T-bet and Eomes are dispensable for IFNg production by CD8+ T cells under optimal Th1 differentiation conditions. However, they are necessary for suppressing alternative fates of CD8+ T cells. They drive Tc1 differentiation by preventing alternative CD8+ T cell differentiation to Tc17 or Tc2 cells. Surprisingly, T-bet and Eomes are not critical for the generation of systemic CTL activities against tumor cells. Instead, T-bet and Eomes are crucial for T cell migration and retention in the tumor site and elimination of solid tumors by CD8+ T cells through regulating chemokine receptors such as CXCR3 and IFNg expression in tumor microenvironment. Therefore, our study establishes T-bet and Eomes as key regulators of adaptive cell-mediated immunity against cancer.
Cytotoxic mechanisms of IL-4 polarized CTLs (101.28)
Authors: Hudig Dorothy , McKinney Christopher , Alves Bryce , Tamang David , Redelman Doug , Singer Cherie , Elliott Viki 
Published: January 2023

Abstract
IL-4 down-regulates perforin and granzymes and depresses rapid (4 hr) cytotoxic T lymphocyte (CTL) killing. Curiously, IL-4 can increase anti-tumor immunity in animal models. We wanted to know how IL-4 polarized CTLs kill and found that they have potent delayed cytotoxicity. We cultured BALB/c mouse splenocytes with conA and 500 units/ml mouse IL-4 or IL-2 for 3 days and then re-cultured the cells for 3 days with cytokines without conA. The IL-4 CTLs were polarized as indicated by expression of the IL-4 inducible lipase PLRP2. By flow cytometry, IL-4 CTLs expressed Grz B at lower levels than IL-2 CTLs. We assayed cytotoxicity using anti-CD3-redirected death of P815 tumor cells. Death was measured at 48 hrs by loss of EGFP+ P815 cells using flow cytometry with cell count beads to account for dead cell disintegration. Cytotoxicity by the IL-4 CTLs was 80% at effector lymphocyte to P815 (E:T) ratios of 1:10. IL-4 CTLs had perforin-independent mechanisms, with similar activity for WT and Prf1-/- CTLs. We monitored T cells for death receptor ligands. Quantitative RT-PCR indicated that IL-4 cells maintained comparable levels of mRNA for LTβ, LIGHT, TRAIL and FasL, but had lower levels of TNFα and TNFβ, than IL-2 CTLs. We conclude that IL-4 polarized CTLs have potent cytotoxicity which could be mediated by death receptor ligands and/or by novel IL-4 inducible potential cytotoxins. Supported in part by NIH grants R01CA38942, T32CA09563, P20 RR-016464 & P20-RR015581.