bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of CXCR3 in the microenvironment of chronic lymphocytic leukemia
Authors: Rößner Philipp M. , Hanna Bola S. , Zenz Thorsten , Stilgenbauer Stephan , Lichter Peter , Seiffert Martina 
Published: January 2023

Abstract
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy that is stringently associated with a tumor-supportive microenvironment and defective anti-tumor immunity. T cells from CLL patients show features of exhaustion, including expression of PD-1, and are highly impaired in their activity.
Our previous work showed that immune checkpoint blockade using anti-PD-L1 effectively prevents disease and restores T-cell activity in the Eμ-TCL1 mouse model of CLL. Development of disease in these mice was shown to be associated with a relative loss of naïve T cells and an enrichment of effector T cells displaying an exhausted phenotype. Our work showed that T cells in the Eμ-TCL1 mice express high levels of the chemokine receptor CXCR3 accompanied with elevated serum levels of the corresponding chemokines CXCL9 and CXCL10, suggesting a role for CXCR3 in T-cell skewing in CLL. Intracellular flow cytometric analysis showed an enrichment of CXCL9+ CD45+ hematopoietic cells in leukemic spleens which were identified as Ly6C+ monocytes. Along this line, depletion of phagocytic cells by Clodronate Liposomes resulted in significantly decreased serum levels of CXCL9, a reversal of T-cell skewing and slowed down development of CLL in mice. To evaluate the role of this receptor in CLL in vivo, adoptive transfer of murine CLL cells in CXCR3 knockout mice is currently ongoing. We further perform an in-depth phenotypical analysis of T-cell subsets in blood samples of CLL patients from different prognostic subgroups to characterize T-cell aberrations along with disease progression. Taken together, our data suggest a pathomechanistic role for CXCL9, CXCL10 and their receptor CXCR3 in CLL. Their potential as novel drug targets needs to be explored in the future.
DUB-3 regulation of tumor associated inflammation and tumor growth
Authors: Lu Chih-hao , Yeh Da-Wei , Lai Chao-Yang , Liu Yi-Ling , Chuang Tsung-Hsien 
Published: January 2023

Abstract
The tumor microenvironment includes blood vessels, immune cells, fibroblasts, and tumor cells. Inflammation in tumor microenvironment leads to the initiation, promotion, invasion, and metastasis of cancer. Inflammation stimuli such as TNF-α, IL-1β and TLR ligands are capable of activating the NF-κB controlled inflammatory signaling in cancer cells. The activations by these stimuli are modulated by various signaling molecules including those control ubiquitination and deubiquitination in the NF-κB signaling pathway. The DUB-3, has been identified as a deubiquitinating enzyme that belongs to cytokine inducible DUBs. In this study, we investigated the function of DUB-3 in control of inflammatory responses in different cancer cells. Expression of DUB-3 in these cancer cells regulated IL-1β, LPS, and Pam3Cys induced cytokine and chemokine productions and generated favorable conditions for tumor growth. DUB-3 promoted in vivo tumorigenesis and tumor growth. H&E staining of tumor sections revealed higher leukocyte infiltration in the tumors. The expression of genes associated with inflammation were investigated, and higher expression of inflammatory cytokines and chemokines were observed in tumors. Taken together, these observations suggest that DUB-3 regulates tumor growth by modulating inflammatory associated function.
Enterobacteria-mediated the overproduction of intestinal exosomes S1P to drive Th17-mediated colon tumor growth
Authors: Deng Zhongbin , mu jingyao , Zhuang xiaoying , zhang lifeng , Haribabu Bodduluri , Miller Donald , zhang huang-ge 
Published: January 2023

Abstract
The tumorigenic function of exosomes has become widely recognized. However, the potential role of intestinal mucosa-derived exosome-like nanoparticles (IDENs) in the regulation of the intestinal immune system of a colon tumor–bearing host has not been studied. We hypothesize that, along with epithelial cells, intestinal bacteria and immune cells, IDENs in the intestinal mucosa play a crucial role in gut immune regulation. We find that enterobacteria-secreted particles (ET-BSPs)induce the overproduction of exosome-like nanoparticles from gut mucosal cells. These nanoparticles promote colon cancer by influencing the recruitment and proliferation of Th17 cells in the intestine. A key component of these bacterially induced nanoparticles is their ability to induce the production of lipid sphingosine-1-phosphate in mucosal cells. Moreover, the release of sphingosine-1-phosphate causes elevated levels of chemokine (C-C motif) ligand 20 (CCL20) and prostaglandin E2 (PGE2) in the exosome-like nanoparticles. CCL20 and PGE2 are required for the recruitment and proliferation, respectively, of Th17 cells, and these processes also involve the MyD88-mediated pathway. We demonstrate the biological effect of sphingosine-1-phosphate production by exosome-like nanoparticles on tumor growth in APCMin/+ and MC38 tumor-bearing mouse models. These findings provide deeper insights into how host-microbe relationships are mediated by particles secreted from both bacterial and host cells
Chronic Lymphocytic Leukemia-Derived Extracellular Vesicles Mediate NFκB Signaling and Pro-Inflammatory Cytokine Release in Monocytes
Authors: Seiffert Martina , Haderk Franziska , Cid Laura Llao , Göbel Maria , Dürig Jan , Lichter Peter 
Published: January 2023

Abstract
Chronic lymphocytic leukemia (CLL)is a B-cell malignancy associated with an inflammatory milieu and impairedanti-tumor immunity. This study aimed at characterizing CLL-derived extracellularvesicles (EVs) and their role in the tumor microenvironment.
EVs were isolated from blood plasma or culture supernatant of the CLL cell line MEC-1 by a serialcentrifugation protocol. Characterization of EVs by electron microscopy, Nanoparticle Tracking Analysis (NTA) and Western blotting revealed vesicles 30to 350 nm in size, which were positive for various EV marker proteins. Quantificationof EVs by NTA and ELISA indicated an enrichment of B-cell derived EVs in plasmaof CLL patients compared to healthy controls, although absolute EV counts were not different. As we observed an accumulation of small RNAs in EVs, small RNAsequencing was performed which revealed a unique microRNA signature of MEC-1 EVs, with CLL-relevant miRNAs such as miR-21, miR-155 and miR-146a being the mostabundant. Moreover, full length and 5′ end fragment forms of Y RNAs, another class of small non-coding RNAs, were enriched in MEC-1 and CLL plasma EVs. In vitro and in mice, CLL EVs were rapidly taken up by monocytes and macrophages which resulted in NFκB signaling and the release of multiple pro-inflammatory cytokines such as CCL2, CCL3, IL-6 andIL-8, proteins known to be elevated in CLL plasma. Moreover, several surface markers on monocytes were altered upon EV uptake, including an increase of the immune checkpoint molecule PD-L1 as well as downregulation of the chemokine receptorCCR2. Of interest, liposomes containing Y RNA transcripts induced a similar response in respective assays suggesting a novel role for these molecules in the tumor microenvironment of CLL.
Creating a T cell-inflamed tumor microenvironment overcomes resistance to checkpoint blockade
Authors: Tang Haidong , Wang Yang , Chlewicki Lukasz K , Zhang Yuan , Fu Yang-Xin 
Published: January 2023

Abstract
Recent clinical trials with checkpoint blockade antibodies have shown unprecedented durable responses in some patients with a variety of cancers. However, such therapies fail to induce responses in majority of cancer patients. How to increase the objective response rate becomes an urgent challenge. A T cell-inflamed tumor microenvironment is associated with clinical responses to immunotherapies, including checkpoint blockades. Previous studies in our lab have shown that local expression of the tumor necrosis factor superfamily member LIGHT (also known as TNFSF14) by tumor cells may promote the formation of lymphoid-like structures for direct T-cell sequestration and activation, leading to tumor regression. To better evaluate the therapeutic efficacy of LIGHT, we target LIGHT to tumor tissues through an antibody-LIGHT fusion protein. We demonstrated that targeting tumors with LIGHT activates lymphotoxin b receptor signaling, leading to the production of chemokines that recruit massive numbers of T cells. Furthermore, targeting non-T cell-inflamed tumor tissues by antibody-guided LIGHT creates a T cell-inflamed microenvironment and overcomes tumor resistance to checkpoint blockade. Our study indicates that targeting LIGHT may be an effective strategy for cancer immunotherapy, especially those who do not response to checkpoint blockade due to the lack of infiltration.
MEK inhibition by trametinib impairs the mobilization of monocytic MDSCs to facilitate anti-tumor T cell immunity
Authors: Allegrezza Michael , Svoronos Nikolaos , Perales-Puchalt Alfredo , Payne Kyle K , Nguyen Jenny , Conejo-Garcia Jose R 
Published: January 2023

Abstract
The MEK inhibitor trametinib is approved for clinical use in melanoma and being investigated in many other solid tumors, yet the effects of trametinib on non-tumor cells in the cancer microenvironment remain understudied. Although MEK inhibition potently suppresses T cells in vitro, cytotoxic T cell activity is unaffected in trametinib-treated mice. In a preclinical Kras-driven breast cancer model we found that the anti-tumor activity of trametinib requires CD8+ T cells and occurs even in the absence of direct inhibition of tumor cell proliferation. Instead, trametinib selectively impairs the mobilization of Ly6C+ Myeloid-Derived Suppressor Cells (MDSCs) from myeloid precursors and also abrogates the production of MDSC-chemotactic osteopontin by tumor cells. These combined effects reduce MDSC accumulation at tumor beds, enhancing T cell-mediated protection. Our results demonstrate that the combined anti-inflammatory activity of trametinib on multiple cell types, even without direct influence on tumor cell proliferation, could be responsible for its anti-tumor effects.
CCL3 in the tumor microenvironment augments the antitumor immune response
Authors: Allen Frederick , Bobanga Iuliana , Barkauskas Deborah , Myers Jay , Huang Alex Y. 
Published: January 2023

Abstract
CCL3 is important in orchestrating cellular contacts in vaccinated lymph nodes (LNs) and enhancing memory T cell generation. Furthermore, dendritic cells (DCs) have been shown to mediate both tumor-tolerance and antitumor immunity in some tumor models. We hypothesize that incorporating CCL3 into tumor vaccines can enhance antitumor immunity. We injected into the footpad of naïve recipients, wild-type tumors (WTTUs) or CCL3-secreting (L3TUs) colon tumors (CT26). Immunocompetent mice injected with L3TUs resulted in a suppression of tumor growth compared to the WTTU group in a CD8+ T cell dependent manner. 1- and 5- days after injection with WTTUs or L3TUs, there was a superior accumulation of endogenous DCs and activated T cells in the draining lymph node (DLN) of the L3TU group. Concurrently bone marrow dendritic cells (BMDC)-tumor or -T cell co-culturing experiments were conducted to assess the effects the tumor and its microenvironment (+/− CCL3) has on DC function. In vitro experiments using BMDCs cultured with CCL3 enhanced their expression of MHC-I, CD86, and CCR7. BMDCs cultured with CCL3, then pulsed with SIINFEKL peptide, also showed an enhance capacity to proliferate OT-I (CD8+) T cells. In vivo analysis reveal that BMDCs injected directly into mice bearing L3TUs showed an enhanced ability to home to DLNs. Moreover, ElISpot and intracellular analysis of isolated T cells from LNs revealed an enhanced ability for T cells to upregulate IFNγ post-tumor injection with L3TUs. Together these data reveal that CCL3 in the tumor microenvironment leads to a reduction in tumor growth and improved T cell responses in the DLN, which may be a result of an enhanced capacity for DCs to home to the DLN and activate antitumor T cells.
Aβ vaccination in conjunction with bee venom derived phospholipase A2 (bvPLA2) ameliorates Alzheimer’s disease pathology through the induction of Aβ-specific Treg population in 3xTg-AD mice
Authors: Bae Hyunsu , Baek Hyunjung , Ye Minsook , Kang Geun-Hyung , Lee Chanju , Lee Gihyun , Choi Da Bin , Hwang Deok-Sang , Lee Junyoung 
Published: January 2023

Abstract
Alzheimer’s disease (AD) is the most common form of dementia and characterized by an imbalance between the production and clearance of amyloid-beta (Aβ) and tau proteins. Vaccination against Aβ peptide results in dramatic reduction of Aβ pathology in experimental mouse models. Our recent study demonstrated that bvPLA2, the major component of BV, causes immune tolerance by increasing the population of CD4+CD25+Foxp3+ Tregs in cisplatin-induced nephrotoxicity, an allergic asthma and Parkinson disease murine model. Here, we investigated that the effect of bvPLA2 to induce antigen-specific Tregs to ameliorate Alzheimer’s disease (AD) pathology through linked immunosuppression. First, we investigated whether bvPLA2 would improve the cognitive function and the pathological features of AD in Aβ-vaccinated-3xTg-AD mice. bvPLA2 treatment dramatically ameliorated learning and memory deficits in Aβ-vaccinated-AD mice. In addition, bvPLA2 significantly reduced Aβ deposits in the hippocampus and cortex region of AD mice, compared with the Aβ-vaccinated-AD mice group. Next, we systemically administered Aβ-specific Treg populations generated in the absence or presence of bvPLA2 into 3xTg-AD mice. Systemic transplantation of Aβ-specific Tregs into 3xTg-AD mice improved cognitive function and reduced deposition of Aβ plaques. Furthermore, adoptive transfer of Tregs generated in the presence of bvPLA2 showed reduced Aβ plaques and diminished learning and memory ability compared with Tregs generated in the absence of bvPLA2. This opens the possibility of new therapeutic strategy to target Tregs to tissue-specific antigens for the treatment of AD.
Direct activation of iNKT cells by CD1d bound glycolipid antigens leads to a different kinetics of iNKT activation and expansion
Authors: Kharkwal Shalu Sharma , Kharkwal Himanshu , Johndrow Christopher T , Carreno Leandro J , Jervis Peter , Zhang Lianjun , Hui Engyap , Fiser Andras , Zauderer Maurice , Besra Gurdyal S , Donda Alena , Porcelli Steven A 
Published: January 2023

Abstract
Invariant Natural Killer T cells (iNKT) are innate like T lymphocytes that recognize glycolipid antigens bound to CD1d molecule expressed by antigen presenting cells (APCs). iNKT cells modulate many aspects of immune responses and hence are targeted in many immunotherapeutic strategies. However, the prototypical iNKT agonist α-galactosylceramide (α-GC) and its synthetic analogues have limitations that include but are not limited to toxicity and iNKT anergy. Here, we report the development of an iNKT activating tumor targeted tertiary complex composed of a CD1d-antitumor ScFv antibody fusion protein covalently coupled to novel benzophenone linked α-GC analogs (BPGCs). Covalent complexes have dramatically improved stability and higher avidity to iNKT TCR and hence up to ten times lower effective dosage of the complex can stimulate strong immune response. Notably, these complexes directly activate iNKT cells bypassing the need for APCs. Hallmarks of covalent complex mediated iNKT activation include strong and sustained IFN-y secretion with no extensive iNKT proliferation or upregulation of co-inhibitory markers such as PD-1, even after multiple treatments as opposed to free α-GC and non-covalent complexes. In vitro, anti Her2 ScFv.CD1d.BPGC complexes lead to iNKT mediated targeted killing of MC38 cells overexpressing human Her2. Preliminary antitumor immunotherapy experiments in mice have shown that one third of the covalent complex treated mice show substantial reduction in tumor growth, including apparent eradication of tumors in some cases. Altogether, our approach enables a strong iNKT-based immune activation without the need for APCs and provides long lived and localized NKT activation in the tumor microenvironment.
Fucoidan prevents LPS-induced production of nitric oxide and prostaglandin E2 by inhibiting MAPK-mediated signal pathways in RAW 264.7 macrophage cells
Authors: Jang Yong-Suk , Park Jisang , Hwang Seung-Mi , Ko Eun-Sil , Choi Kyung-Min , Cha Jeong Dan 
Published: January 2023

Abstract
Fucoidan is a sulfated polysaccharide that is primarily extracted from brown seaweeds which has been broadly studied in recent years due to its numerous biological properties, including anticoagulant, antithrombotic, antitumor, and antiviral activities. In this study, we investigated whether fucoidan has the ability to attenuate the expression of pro-inflammatory mediators such as NO, prostaglandin E2 (PGE2), TNF-α, and IL-1β in LPS-stimulated RAW 264.7 macrophage cells. Fucoidan inhibited the expression of LPS-induced pro-inflammatory mediators including NO, PGE2, TNF-α, and IL-1β. In addition, gene expression of iNOS, cyclooxygenase-2 (COX-2), TNF-α, and IL-1β was inhibited both at mRNA and protein levels by fucoidan treatment, without any cytotoxic effect. Moreover, fucoidan significantly inhibited LPS-induced NF-κB activity NF-κB translocation into the nucleus by preventing the degradation of iκB-α. Taken together, these results indicate that fucoidan downregulates the expression of pro-inflammatory genes involved in the synthesis of NO, PGE2, TNF-α, and IL-1β in LPS-stimulated RAW 264.7 macrophage cells by suppressing NF-κB activity.
Alternating electric fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy
Authors: Giladi Moshe , Voloshin Tali , Shteingauz Anna , Munster Mijal , Blat Roni , Porat Yaara , Schneiderman Rosa S , Cahal Shay , Itzhaki Aviran , Kirson Eilon , Weinberg Uri , Palti Yoram 
Published: January 2023

Abstract
Tumor Treating Fields (TTFields) are an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. This therapy is approved for the treatment of patients with glioblastoma. Previous investigations have shown that TTFields disrupt microtubules and septin filaments, both of which govern key roles in mitosis. Some of the outcomes of mitosis under TTFields application include abnormal chromosome segregation and ER stress which trigger different forms of cell death. In this study, we demonstrate that application of TTFields leads to the exposure of calreticulin on the surface of different cancer cells in vitro. In vivo, the combined treatment of lung tumor-bearing mice with TTFields and anti-PD-1 led to a significant decrease in tumor volume compared to control group and to animals treated with anti-PD-1 alone. An increase in CD45+ tumor infiltrating cells was observed in both anti-PD-1 and TTFields+anti-PD-1 groups although statistical significance was reached only in the combination treatment group. Interestingly, CD45+ cells from the combination treatment group also demonstrated a significant upregulation of PD-L1 expression on the cell surface. Specifically, this upregulation in the PD-L1 expression was observed in both F4/80+CD11+ cells and CD11c+ cells whereas no significant effect on the infiltration pattern of these immune cell populations was noted. Taken together, our results demonstrate that TTFields application potentiates immunogenic cell death in cancer cells and that combining TTFields with specific immunotherapies such as anti-PD-1 might achieve tumor control by further enhancing antitumor immunity.
Pharmacological activation of the p53 pathway within the tumor microenvironment induces immunogenic cell death of tumors and enhances antitumor immunity
Authors: Cui Yan , Yu Miao , Xiao Wei , Guo Gang 
Published: January 2023

Abstract
The tumor suppressor p53 is the most frequently mutated genes in human tumors. Thus, targeting the p53 pathway is important. Small molecules that activate wild type p53 or revert p53 mutants to wild type conformation have been developed. Despite effective tumor killing, these molecules as mono-therapy fail to reach all tumor cells. Interestingly, recent studies from our laboratory and others showed that p53 inactivation/dysfunction in the TME skews the immunological landscape towards pro-tumor/inflammation. We, thus, propose that activating (re-activating) p53 reverses tumor-induced immunosuppression and enhances antitumor immunity. Here, we examined whether pharmacological activation of the p53 pathway in the TME lead to immunogenic cell death (ICD) of tumors. As expected, tumors maintaining functional p53, such as EL4 and B16, initiated ICD upon treatment with a p53 activator, nutlin-3a, shown as the release of HMGB1 and ATP to extracellular space. Intratumoral injection of nutlin lead to mobilization and activation of immune cells and antitumor immunity. This resulted in tumor regression not only on the side of injection, but also those contralateral to the injection. Moreover, mice experienced completely tumor regression due to nutlin-3a injection rejected the same tumor in subsequent re-challenges. This tumor rejection was mostly mediated by CD8 T cells because it was alleviated by CD8, but not CD4, depletion. Together, our results suggest that p53 activation within the TME serves as a dual agent, direct killing of tumors and subsequent activation of antitumor immunity. Thus, pharmacological activation of p53 can be used in combinational therapies for promoting more durable, specific, and systemic antitumor immunity.
Artificial antigen presenting cells with simultaneously releasing IL-2 and anti-CTLA-4 showed enhanced capability in antigen specific T-Cells activation and tumor inhibition
Authors: Zhang Lei , Zhang Yi-Ming , Shahzad Khawar Ali , Shen Chuan-Lai 
Published: January 2023

Abstract
Artificial antigen presenting cells (aAPCs) are thought to be a powerful tool to induce antigen specific T cells responses. Thus far, aAPCs were synthesized by coupling antigen specific signals (signal 1) and the co-stimulatory molecules (signal 2) onto microparticles surface. To fully activate and proliferate antigen specific T cells, the optimized aAPCs should be consider signal 3 in the form of various cytokines secretion.
IL-2 and anti-CTLA-4 are both effective immunotherapeutic agents for tumors. Therefore, encapsulating these two important molecules into aAPCs might increase their stimulating function through modulation of two oppositely cell signaling pathways.
Here, we prepared aAPCs with simultaneously releasing IL-2 and anti-CTLA4 (aAPCIL-2+ anti-CTLA4) based on PLGA microparticles. A high density of functional molecular ligands for recognition (H-2Kb/TRP2) and co-stimulation (anti-CD28) of T cells were attached to the particles surface.
Our results showed that a suitable aAPCIL-2+ anti-CTLA4 were fabricated successfully, IL-2 and anti-CTLA-4 were released in a sustained manner. Our modified aAPCIL-2+ anti-CTLA4 showed an enhanced capability to generate and expand antigen specific T cells. Furthermore, the aAPCIL-2+anti-CTLA4 generated T cells displayed more effective specific killing abilities. In addition, in vivo studies also demonstrated an enhanced tumor inhibition capability over traditional aAPCs.
Thus, the novel aAPC system aAPCIL-2+ anti-CTLA4 we fabricated here showed a unique potential to enhance the application of the aAPC technology for future immunotherapy approaches.