bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the tumor microenvironment with the monoclonal antibody Tocilizumab, reduces IgM secretion in Waldenström macroglobulinemia
Authors: Han Weiguo , Matissek Stephan Josef , Jackson David , Sklavanitis Brandon , Elsawa Sherine F. 
Published: January 2023

Abstract
The tumor microenvironment (TME) plays an important role in cancer and has been shown to play a role in resistance to therapy and is therefore important in cancer cell biology. In Waldenström macroglobulinemia (WM), a B cell malignancy characterized by the overproduction of a monoclonal IgM protein, the TME secrets cytokines that promote malignant phenotype. In previous work, we have shown that TME-IL-6 promotes WM cell growth and IgM secretion in WM. Tocilizumab/Actemra is an anti-IL-6R antibody, which can competitively block IL-6 binding to the IL-6R. Here we investigated the efficacy of Tocilizumab in a preclinical mouse model of WM that considers the role of the TME in disease biology. Hairless SCID mice were injected subcutaneously with BCWM.1 or RPCI-WM1 and bone marrow stromal cells (HS-5) at a ratio of 5:1. Groups of mice with treated with Tocilizumab or control antibody three times/week for 5 weeks and the effect on tumor burden and disease biology were evaluated. Although Tocilizumab had no effect on mice survival, there was a reduction in tumor growth rate in mice injected with RPCI-WM1 cells + stromal cells and treated with Tocilizumab (p=0.0394). In mice injected with BCWM.1 + stromal cells, there was a significant reduction in human IgM secretion in mice sera with Tocilizumab treatment (p=0.0099). There was no significant change in mice weight suggesting Tocilizumab induced no toxicities to the mice. Taken together, our data suggests that administration of Tocilizumab to tumor bearing mice, results in a significant reduction in tumor volume and IgM secretion. Therefore, the evaluation of the role of Tocilizumab in WM patients may provide therapeutic efficacy by reducing IgM production and slowing the rate of tumor growth.
Hypoxia-Inducible Factor-1α is upregulated in Natural Killer cells by Interleukin-2 and hypoxia via PI3K/mTOR signaling pathway
Authors: Cluff Emily R , Nolan Joshua , Collins Cortney , Varadaraj Archana , Rajasekaran Narendiran 
Published: January 2023

Abstract
Natural killer (NK) cells have cytotoxic functions that aid in the recognition and killing of tumors. Hypoxia is a major characteristic of the tumor microenvironment (TME) and cellular adaptive responses are mediated by hypoxia inducible factors (HIFs). This study investigates how activated NK cells adapt to hypoxia through the upregulation of HIF-1α. Both NK cell lines, NKL and NK92, upregulated HIF-1α when exposed to hypoxia but only when stimulated with IL-2. NKL cells activated with IL-2 and exposed to 5% O2 did not increase expression of HIF-1α. Treatment with translational inhibitor cycloheximide (CHX) blocked HIF-1α expression indicating that the IL-2 mediated signaling stimulates HIF-1α protein synthesis under hypoxia. The synthesis of HIF-1α through IL-2 induced signaling via the PI3K/mTOR pathway was essential for HIF-1α expression by NK cells under hypoxia. Treatment of PI3K inhibitor LY294002 or mTOR inhibitor Rapamycin blocked the expression of HIF-1α, while MAPK inhibitor PD98059 had no effect on IL-2 stimulated NKL cells. Importantly, NKL cells exposed to hypoxia demonstrated a reduced anti-tumor cytotoxicity against the colorectal cancer cell line DLD-1 in a real time impedance-based cytotoxicity assay (xCelligence RTCA). Similar results were obtained with NK-92 cells and primary NK cells derived from human PBMCs. Increase in HIF-1α expression under hypoxia were observed in NK cells treated with IL-15, another common cytokine receptor gamma chain cytokine. Together, these data illustrate that the activation of the PI3K/mTOR signaling pathway through the common cytokine receptor gamma chain is critical for HIF-1α upregulation in NK cells under hypoxia and provide a molecular basis for reduced NK cell functions.
Immune cell phenotype and cytokine secretion in mouse breast cancer responding to anti-CD47 antibody treatment
Authors: wen Chiao Kai , Elia Jeanne , Loter Lorraine , RAFIZADEH TANNAZ , Jiang Weiping , Zhang Hong , Yang Xifeng 
Published: January 2023

Abstract
Anti-CD47 antibodies have been shown to inhibit the progression of several types of cancer by blocking the “don’t eat me” signals to macrophage through CD47/SIRPα interaction, causing phagocytosis of tumor cell. However, mechanistic details in the response of the cancer cells still remain to be explored. In this study, we investigated different cytokine levels in 4T1 mammary carcinoma induced mouse breast cancer model with or without anti-mouse CD47 monoclonal antibody treatment. The data showed that this cancer model presented significantly higher percentages of CD11b+, CD43+, CD80+, CD86+ and CD371+ cells after 1 week of 4T1 cells injection, CD11b+ cells percentage has been reached to 40% and 90% in spleen and bone marrow respectively at 2 weeks after 4T1 cells injection. After 4 doses of anti-mouse CD47 antibody treatment (i.p. injection per 2 days started from one week after 4T1 challenge), anti-CD47 antibody reduced significantly not only tumor size but also the levels of IL-1α in spleen (P=0.026) and of MCP-1/CCL2 in tumors (P=0.029). Interestingly, fresh isolated 4T1 induced breast cancer mouse spleen and bone marrow cells appeared 5%-10% CD11b+/Sca-1+ populations whereas in vitro culture of 4T1 cells had 5% of cells of Sca-1+/CD326+. When the freshly isolated 4T1 induced breast cancer mouse spleen and bone marrow cells were continuously cultured for 2–3 weeks, CD326+ cells became dominant and about 10% – 30% of population showed Sca-1+/CD11b+ positive. This study provided inside thoroughly investigated the response of cytokines and 4T1 cells induced mouse mammary carcinoma. Our data may further discover the mechanism for tumor growth and metastasis.
Quantification of A Spectrum of Adhesion Molecules in Metastatic Cancer Patient Samples Using a Multiplex Bead-Based Immunoassay Panel
Authors: Zhao Amy , Lehmann Jason , Sun Binggang , Jiang Weiping , Ji Shaoquan 
Published: January 2023

Abstract
Metastasis to distant organs is responsible for ~90% of cancer-related deaths. Adhesion molecules are cell surface proteins that mediate the interactions between disseminated tumor cells and the endothelium of blood vessels present in the tumor microenvironment, and thus play a major role in tumor metastasis. Serum and plasma samples from patients with metastatic disease (head, neck, breast, pancreatic, gastric, and lung cancer patients) or healthy controls were assayed with a bead-based multiplex immunoassay which measured the concentration levels of the following adhesion molecules: ICAM-1, ICAM-2, ICAM-3, VCAM-1, PECAM-1, ALCAM-1, EpCAM, NCAM, E-selectin, P-selectin, L-selectin, PSGL-1, and CD44. Although limited by sample size, differential concentrations of assay targets were detected between healthy and disease-state samples. We have demonstrated that this multiplex panel is a robust tool for measuring the concentration of a spectrum of adhesion molecules with great efficiency and convenience. This panel will help screen and identify the adhesion molecules that may be universally or specifically involved in metastasis of different types of cancer.
Virus-specific memory T cells populate tumors and can be repurposed as a tumor immunotherapy
Authors: Rosato Pamela , Wijeyesinghe Sathi , Stolley Michael , Nelson Christine , Davis Rachel L , Manlove Luke S , Pennell Christopher A , Blazar Bruce R. , Chen Clark C , Geller Melissa A , Vezys Vaiva , Masopust David 
Published: January 2023

Abstract
The immunosuppressive tumor microenvironment limits the success of current immunotherapies. The host retains memory T cells specific for previous infections throughout the entire body that are capable of executing potent and immediate immunostimulatory functions. Here we show that virus-specific memory T cells extend their surveillance to mouse and human tumors. Reactivating these antiviral T cells can arrest growth of checkpoint blockade-resistant and poorly immunogenic tumors in mice after injecting adjuvant-free non-replicating viral peptides into tumors. Peptide mimics a viral reinfection event to memory CD8+ T cells, triggering antigen presentation and cytotoxic pathways within the tumor, activating dendritic cells and natural killer cells, and recruiting the adaptive immune system. Viral peptide treatment of ex vivo human tumors recapitulates immune activation gene expression profiles observed in mice. Lastly, peptide therapy renders resistant mouse tumors susceptible to PD-L1 blockade. Thus, re-stimulating known antiviral immunity may provide a unique therapeutic approach for cancer immunotherapy.
Adipocyte PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Cancer Immunotherapy Efficacy
Authors: Wu Bogang , Sun Xiujie , Gupta Harshita B. , Curiel Tyler J , Li Rong 
Published: January 2023

Abstract
PD-L1 expression in both tumor and host cells correlates with antitumor therapeutic efficacy, but the specific contribution of PD-L1 in various cell compartments to antitumor immunity remains to be fully elucidated. Here we show that PD-L1 expression is significantly elevated in human and mouse mature adipocytes versus preadipocytes. When co-cultured with mouse splenocytes, adipocytes reduce αPD-L1 antibody-mediated CD8+T cell activation. Genetic ablation of adipose PD-L1 obliterates, while enforced PD-L1 expression in preadipocytes confers, the immune-inhibitory effect of adipocytes. Pharmacologic inhibition of adipogenesis by the PPARγ antagonist GW9662 reduces adipose PD-L1 expression and enhances the antitumor efficacy of αPD-L1 and αPD-1 immunotherapies in female mice bearing syngeneic melanoma or mammary tumors. Combo treatment with GW9662 and αPD-L1 increased antitumor lymphocytes infiltration versus control or single agent treatment. In diet-induced obese female mice, combo treatment elicited suppressed melanoma growth, although less effectively versus lean females. In contrast to females, melanomas in either lean or obese male mice exhibited no applicable response to combo treatment. More strikingly, obese males lost αPD-L1 single treatment response versus lean males, with lower CD45+and CD3+T cell infiltration in tumors. However, castration in lean males rescued efficacy of combo treatment. These data suggest an antagonistic effect of male hormones in this combination. The potential impact of sex and obesity warrants consideration in future development of immunotherapy-related combination therapy.
B7H3 regulates tumor-mediated Th1 type immune responses
Authors: Lee Jun Sik , Kim Mi Eun , Cho Jun Hwi 
Published: January 2023

Abstract
B7H3 is a new molecule that can regulate T cells-mediated immune responses. Several studies suggested a costimulatory function for B7-H3 in murine models of cancer. In contrast, clinical association of B7-H3 expression suggested a coinhibitory role. The physiological role of B7-H3 is still unclear. To investigate the B7-H3 functions on T cell activation, we used the B7-H3 peptide, B7-H3 negative and overexpressed tumor cells. To establish the T cell inhibitory gene database by B7-H3, we performed the microarray. In the results, B7-H3 inhibited the T cell proliferation and production of cytokines including IL-2 and IFN-γ. We identified the 12 significant effective genes, and confirm the mRNA expression by real-time PCR. These results suggest that B7-H3 showed the co-inhibitory role on T cell functions. And further study is needed to identify the receptor and mechanism of B7-H3 on T cell function.
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2017R1D1A1B03034673), Korea.
MyD88 dimerization inhibitors for targeting Diffuse Large B-cell Lymphomas
Authors: Snyder Greg A , Brown Lindsey , Faupel Ciara , Taylor Savannah , Sherman Matthew , Beadenkopf Robert , Montague Justin , Saikh Kamal , Wang Yajing 
Published: January 2023

Abstract
A recurring single amino acid somatic mutation associated with human diffuse large B cell lymphomas (DLBCLs), correlates with tumor cell proliferation and survival involving spontaneous and sustained activation of MyD88-dependent NF-κB and Janus Kinase (JAK) signaling pathways. MyD88 acts as a central signaling adapter for mediating innate and cytokine driven inflammation for the Interleukin-1 (IL-1R) and Toll-like receptors (TLRs). Computer aided molecular modeling of MyD88 and in silico screening have identified and functionally characterized MyD88 specific small molecule compounds shown to protect against Staphylococcal enterotoxin B (SEB) induced death in animal models. We hypothesize that MyD88 specific small molecule compounds may also be useful in treating DLBCLs bearing the oncogenic mutation MYD88L265P. Using in vitro and in vivo studies we evaluate MyD88 specific small molecule compounds for the ability to inhibit tumor cell proliferation and signaling in human patient cancer cells OCI Ly3 bearing the oncogenic mutation MYD88 L265P and OCI Ly19 DLBCLs. Previously we identified differences in the ability of MyD88 small molecule compounds to inhibit cell proliferation in activated human B cell lymphoma cells bearing the MyD88 L265P mutation. We now correlate these differences with a reduction of MyD88 interaction with IRAK in small molecule treated OCI-Ly3 cells bearing the MYD88 L265P mutation in comparison to OCI-Ly19 (wt-MyD88) and treated controls, as measured by CoIP. We continue to characterize MyD88 specific small molecule compounds that target MyD88 dimerization for their ability to reduce MyD88 containing signaling complexes in DLBCLs bearing MYD88 L265P mutation.
Host genetic background affects response to immune checkpoint inhibitors in a B16 melanoma model using Diversity Outbred mice
Authors: Hackett Justin , McCarthy Claire , Muniz Maria , Malysa Agnes , Wiesend Wendy , Gibson Heather 
Published: January 2023

Abstract
Historically metastatic melanoma has been associated with poor prognosis. The advent of immune checkpoint inhibitors targeting CTLA-4 and PD-1 have greatly improved patient survival in metastatic melanoma, but a significant proportion of patients fail to respond to therapy. To explore the effect of genetic background on immune checkpoint inhibitor efficacy, we have developed a tumor immunotherapy model using genetically heterogeneous Diversity Outbred (DO) mice and the C57BL/6 syngeneic B16F0 melanoma model. To implement genetic diversity, DO mice were crossed with C57BL/6 to generate (C57BL/6xDO)F1 mice. Untreated (C57BL/6xDO)F1 mice (n=17) reliably develop B16F0 tumors after subcutaneous inoculation, with some variation in tumor onset (8.2 +/− 4.1 days, CV 49.9%). In a pilot immunotherapy study, 20 (C57BL/6xDO)F1 mice were treated with anti-PD-1/anti-CTLA4 on days 12, 14, and 16, after tumors were palpable (mean onset 6.8 +/− 4.6 days, CV 68.2%). Tumor tissue was collected on day 19 and CD8 T cell infiltration was analyzed by IHC and qPCR. Mice with reduced tumor growth showed an increase presence of CD8+ cells and IFN-g expression. To further test the role of genetics in response, a second cohort of C57BL/6xDO)F1 mice (n=95) was treated with combined anti-PD1/anti-CTLA-4 on days 3, 6, and 10 after B16F0 inoculation. In this larger trial, mice receiving therapy show wide variation in tumor onset up to 61 days (mean 13.6 +/− 8.9, CV 65.2%), with 10 never developing tumor by day 88. This data further suggests that the genetic background significantly influences response to treatment and validates further testing of this model and subsequent Quantitative Trait Locus analysis. Supported by NIH R37 CA220482.
TSLP modulates anti-tumor Th2 immunity to melanoma via regulation of the PD-L2/PD-1 axis
Authors: Lai Jen-Feng , Thompson Lucas , Ziegler Steven F 
Published: January 2023

Abstract
The cytokine Thymic Stromal Lymphopoeitin (TSLP) has generally been ascribed with both suppressive and stimulatory roles in the context of tumor immune responses. Typically, TSLP-mediated tumor immunosuppression has been attributed to Th2 skewing of T cell responses; here we show that overexpression of TSLP in skin enhanced Th2 anti-tumor immunity to melanoma while deficiency of host expressed TSLP resulted in increased tumor growth. The effect of TSLP-mediated tumor immunity requires TSLP signal in host cells, resulting in elevated infiltration of PD-1+ Th2 CD4 T cells required for the response. Additionally, expression of PD-L2 on tumor-infiltrating antigen presenting cells (APCs) was enhanced by TLSP overexpression; conditional knockout of TSLP receptor on CD11c-expressing cells negated this effect. Disruption of PD-L2 signaling by genetic manipulation or antibody-mediated blockade of PD-L2 reduced infiltration of functional Th2 cells and abolished TSLP-mediated enhanced anti-tumor activity. These results suggest that anti-melanoma Th2-PD-L2/PD-1 axis is potentiated by TSLP to provide effective anti-tumor immunity. These findings provide novel cellular mechanistic insights for potential immunotherapeutic strategies.
MHCII density only weakly impacts autoreactive germinal center B cell fitness
Authors: Wittenborn Thomas Rea , Hagert Cecilia , Ferapontov Alexey , Jensen Lisbeth , Degn Søren Egedal 
Published: January 2023

Abstract
B cells generate high-affinity antibodies within induced microanatomical structures called germinal centers (GCs). Each GC is, in essence, a Darwinian microcosm, in which B cells undergo consecutive rounds of division, hypermutation, and selection based on antigen affinity. The consensus has been that this selection is governed by T follicular helper (Tfh) cell signals, determined by the amount of cognate peptide presented by B cells on major histocompatibility complex (MHC) class II. This view was recently challenged by observations in a foreign antigen model system suggesting that peptide-MHCII density dictates the degree of initial GC entry, but does not impact B cell selection once in the GC. GCs are central to the development of pathogenic autoantibodies in a breadth of autoimmune diseases, but it is unclear to what extent autoreactive GC behavior mimics that of foreign-antigen-reactive GCs. The question of peptide-MHCII in autoreactive GC fitness is particularly relevant because the linked recognition requirement provides a safeguard against inadvertent autoreactivity. Accordingly, we investigated the role of peptide-MHCII density in self-reactive GC B cell selection in a chimeric mouse model of epitope spreading. Bone marrow chimeras were generated, in which either MHCII null/b or MHCII null/null cells were competing with MHCII b/b cells for participation in chronic autoreactive GCs. Flow cytometry and confocal analysis of GCs revealed that whereas complete MHCII deficiency blocked B cell participation in the GC, partial MHCII deficiency had only a minor impact on GC fitness. Thus, our results confirm, in an autoreactive setting, the recently reported observation of MHCII haplosufficiency in foreign antigen responses.
Defining altered regulome structured in response to antigen co-receptors, toll-like receptors, and cytokine receptors stimuli to predispose early developing B cells for pathogenic fate in Systemic lupus erythematosus
Authors: Saini Ankur , Duan Meixue , Mi Tian , Hicks Sakeenah , Lee Eun-Hyung , Scharer Christopher D. , Boss Jeremy M , Gibson Greg , Sanz Ignacio 
Published: January 2023

Abstract
A TLR7-IFNg driven IL-21 mediated unique extra-follicular pathway of ASC differentiation of activated naïve B cells through an intermediary DN2 B cell subset has been characterized in pathogenesis of SLE. It has been correlated to distinct priming of naïve B cells characterized by the presence of SLE disease signatures which indicates towards the convergence of TLR, and cytokine signaling along with BCR signaling in the expansion and differentiation of peripheral B cells in SLE. Thus, we hypothesize that distinct combinations of innate, cytokines and antigen driven stimuli cause pathogenesis of SLE by maneuvering disease-related epigenetic programs and molecular networks during B cell development resulting in perturbed activation and differentiation. Indeed, initial data from bulk RNA-seq show enrichment of Type I interferon production and signature genes in HSCs to transitional B cells in SLE BM. Confounded by scRNA-seq, these populations also show profound type II interferon signature genes in SLE BM. Interestingly, BCR devoid Pro-B cells show reduced expression of BCR signaling intermediates with enhanced proliferation. However, expression of Pre-BCR or BCR on the surface of Pre-B cells or Immature B cells respectively are accompanied by increased expression of BCR co-receptors in SLE BM. On the other hand, metabolically SLE early BM B cells are less dependent on oxidative phosphorylation with reduced protein synthesis and processing. Together, these initial findings provide evidence that the proinflammatory microenvironment in SLE BM exerts its effect by differentially regulating BCR signaling factors and co-receptors in early B cell populations and thereby could define the pathogenic fate of B cell in periphery in SLE.
Metformin enhances the immunomodulatory potential of adipose-derived mesenchymal stem cells through STAT1 in an animal model of lupus
Authors: Jang Se Gwang , Lee Jaeseon , Hong Seung-Min , Kwok Seung-Ki , Cho Mi-La , Park Sung-Hwan 
Published: January 2023

Abstract
Mesenchymal stem cells (MSCs) are considered potential therapeutic agents for treating autoimmune disease because of their immunomodulatory capacities and anti-inflammatory effects. However, several studies have shown that there is no consistency in the effectiveness of the MSCs to treat for autoimmune disease. In this study, we investigated whether metformin could enhance the immunoregulatory function of MSCs, what mechanism is relevant, and whether metformin-treated MSCs could be effective in an animal lupus model. To examine the effects of metformin, adipose-derived (Ad)-MSCs were cultured for 72 h in the presence of metformin. Immunoregulatory factors expression was analyzed by real-time PCR and ELISA. MRL/lpr mice weekly injected 1×106 metformin-treated Ad-MSCs for 8 weeks. Proteinuria, serum anti-dsDNA antibody, lupus nephritis, immune complex, cellular subset were analyzed in each group. Metformin enhanced the immunomodulatory functions of Ad-MSCs including IDO, IL-10, and TGF-β. Metformin upregulated the expression of p-AMPK, p-STAT1, and inhibited the expression of p-STAT3, p-mTOR in Ad-MSCs. STAT1 inhibition by siRNA strongly diminished IDO, IL-10, TGF-β in metformin-treated Ad-MSCs. As a result, metformin promoted the immunoregulatory effect of Ad-MSCs by enhancing STAT1 expression, which was dependent on the AMPK/mTOR pathway. Administration of metformin-treated Ad-MSCs resulted in significant disease activity improvement in MRL/lpr mice. Moreover, metformin-treated Ad-MSCs inhibited CD4−CD8− T cell expansion and Th17/Treg cell ratio. These finding suggest that metformin optimized the immunoregulatory properties of Ad-MSCs and may be a novel therapeutic agent for the treatment of lupus.