bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual-specificity phosphatase 3 knockout female mice are resistant to LPS and to polymicrobial induced septic shock in TNF dependent manner. (P1222)
Authors: Rahmouni Souad , Singh Pratibha , Dejager Lien , Maneesh Singh , Amand Mathieu , Musumeci Lucia , Moutschen Michel , Mustelin Tomas , Libert Claude 
Published: January 2023

Abstract
We report the generation of dual-specificity phosphatase 3 (DUSP3) deficient mice. These mice develop normally and do not exhibit any spontaneous phenotype. However, VHR-/- females, but not males, are resistant to LPS- and to polymicrobial infection-induced septic shock. After LPS injection, while VHR-/- males and VHR+/+ mice of both genders, displayed an increased serum levels of TNF-α and IFNγ, the levels of these cytokines remained significantly low in the VHR-/- females. In vitro experiments using peritoneal macrophages showed the same results suggesting that the systemic cytokines profiles observed are macrophages-dependent. Adoptive transfer of VHR-/- females bone marrow to irradiated VHR+/+ female mice, but not to VHR-/- or VHR+/+ males, protected them from death after administration of LPS. Interestingly, VHR-/- females were sensitive to TNF-α- induced lethality. We also report that the decrease of TNF-α production observed in VHR-/- female’s macrophages after LPS activation was associated with a decreased ERK1/2, but not MEK1/2, activation. Interestingly, pervanadate (PTP pan inhibitor) treatment prior to LPS activation restored ERK1/2 activation in the VHR-deficient macrophages, suggesting that VHR is targeting one of the ERK1/2 PTPs or DUSPs. These results, together with our observation that DUSP3 is the most highly expressed phosphatase in macrophages, suggest a key non-redundant role of VHR as positive regulator of TNF-α in innate immune response in females.
Regulation of naturally-occurring CD4+CD25+ regulatory T cell development by E3 ubiquitin ligase Cbl-b (P1041)
Authors: Zhang Jian , Guo Hui , Qiao Guilin 
Published: January 2023

Abstract
Naturally-occurring CD4+CD25+Foxp3+ regulatory T cells ("nTregs") are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity. CD28 costimulation is essential for the development of nTregs in thymus. E3 ubiquitin ligase Cbl-b has been shown to regulate CD28 dependence of T cell activation. Here, we report that the loss of Cbl-b partially but significantly rescues the defective development of nTregs in CD28-/- mice. This partial rescue is likely to be independent of IL-2 because treating CD28-/- mice with IL-2/anti-IL-2 complex, which has been shown to selectively stimulate nTregs, fails to rescue defective development of CD4+CD8-CD25+Foxp3+ nTregs in thymuses of CD28-/- mice. Mechanistically, Cbl-b binds to Foxp3 upon TCR stimulation, and targets Foxp3 for ubiquitination and subsequently degradation in the proteasome. As Cbl-b self-ubiquitination and proteasomal degradation is impaired in CD28-/- T cells, the defective development of nTregs in CD28-/- mice may in part be due to increased Foxp3 ubiquitination and degradation targeted by Cbl-b. Therefore, we provide a previously-unappreciated function for Cbl-b in regulating Foxp3 expression via an ubiquitination-dependent mechanism.
Scope and mechanisms of peripherally generated regulatory T cell mediated suppression in inflammatory contexts (P1031)
Authors: Niec Rachel , Rudensky Alexander 
Published: January 2023

Abstract
The peripheral Treg population, which prevents fatal autoimmunity in mice and man, consists of Tregs that develop in the thymus (tTregs) and Tregs derived from naïve T cells in the periphery (pTregs). Mice with a specific deficiency in pTregs do not develop the spontaneous multi-organ autoimmunity observed in Treg deficient mice. Instead, specific deficiency in pTregs results in spontaneous Th2 inflammation at mucosal surfaces. While loss of pTreg cells under homeostatic conditions favors Th2 inflammation, we hypothesized that pTregs also participate in control of other types of inflammation, such as induced Th17 inflammation. In a mouse model that is prone to development of spontaneous intestinal Th17 disease, we observed that the absence of pTregs significantly exacerbated Th17 inflammation in intestinal tissues without affecting Th2 inflammation. Next we investigated the potential mechanisms of pTreg mediated T-helper type-specific immune regulation. Unlike tTregs, which enter the periphery as a dedicated suppressor T cell subset, pTregs arise from a precursor population that likely has broad T-helper lineage potential. Here we explore the alternative differentiation of would-be pTregs unable to induce Foxp3 to assess the role of pTreg differentiation as a mechanism of “T-helper immune detraction”. Thus, we explore if Foxp3 induction in the periphery is essential to control a range of inappropriate inflammatory responses and the mechanisms by which this is achieved.
Dasatinib is an effective adjuvant to therapeutic vaccination against melanoma (P4269)
Authors: Lowe Devin , Taylor Jennifer , Tawbi Hussein , Kirkwood John , Storkus Walter 
Published: January 2023

Abstract
Dasatinib (DAS) is an FDA-approved inhibitor of receptor tyrosine kinases (RTKs) (i.e., EphA2 and PDGFRβ) involved in vasculature development/maintenance of solid cancers such as melanoma. Administration of DAS transiently normalizes tumor blood vessels and reduces lesional interstitial pressure, hypoxia, and acidosis (which typically impede the efficacy of standard of care therapies). We hypothesized that DAS-induced vascular changes would lead to improved recruitment of therapeutic effector T cells, particularly after specific vaccination. As a model system, C57BL/6 mice bearing established day 7 subcutaneous B16 melanomas were vaccinated (weekly x 2; VAC) with a tumor-specific DC-based vaccine +/- DAS (i.p. daily for days 7-13). We confirmed that DAS reconditioned tumor blood vessels based on a disruption of hypoxia (reduced expression of HIF-1α/HIF-2α and cancer stem cell markers) and pericyte/endothelial cell architecture. Interestingly, DAS also abrogated systemic frequencies of the MDSC/Treg cell immunosuppressor cell populations. Combination VAC + DAS therapy provided superior anti-tumor protection versus either monotherapy, which correlated with the enhanced trafficking of antigen-specific CD8+ T effectors into tumor lesions. Overall, these results support the clinical translation of this combination immunotherapy for the treatment of melanoma.
WC1 functions as a pathogen-associated molecular pattern receptor and co-receptor for γδ T cells (P6083)
Authors: Telfer Janice , Hsu Haoting , Chen Chuang , Baldwin Cynthia 
Published: January 2023

Abstract
WC1 proteins, expressed on bovine γδ T cells, are members of the scavenger receptor cysteine-rich (SRCR) superfamily and are coded by 13 genes (WC1-1 to WC1-13). Phosphorylation of a tyrosine in the WC1 cytoplasmic domain upon co-ligation of WC1 and TCR is required for WC1 co-receptor activity. Serologically-defined WC1.1+ γδ T cells specifically respond to the spirochete Leptospira; in contrast, WC1.2+ γδ T cells respond to the rickettsiales Anaplasma. Silencing via shRNA suggests that only cells expressing the WC1.1 type gene products WC1-1, WC1-2 or WC1-3 contribute to the γδ T cell response to the spirochete Leptospira, suggesting that expression of individual WC1 receptors encodes antigen specificity through ligation of bacteria. Comparing a representative of WC1 proteins expressed by WC1.1+ Leptospira-responsive cells (i.e., WC1-3) to a representative of WC1.2+ Leptospira-nonresponsive cells (i.e., WC1-4), we found that five out of eleven WC1-3 SRCR domains and none of the eleven WC1-4 SRCR domains bound to two Leptospira species, L. borgpetersenii and L. interrogans. Mutational analysis of WC1-3 SRCR domains suggests that the active site for bacterial binding is different from that previously reported for other SRCR proteins that bind bacteria and also that it is affected by single amino acid changes. Taken together, our data suggest that co-ligation of specific WC1 proteins and the γδ TCR by pathogen-associated molecular patterns (PAMPs) induces γδ T activation.
High level of CD8+ cytotoxic T lymphocyte is essential for eliminating mesothelioma (P2125)
Authors: Tan Zhiwu , Zhou Jingying , Cheung Allen , Liu Li , Chen Zhiwei 
Published: January 2023

Abstract
Mesothelioma presents an aggressive human cancer in the lungs of people exposed to asbestos. Although immunotherapy is a way of treatment, the type of immune response that eliminates mesothelioma remains poorly defined. Here, we developed a quantitative mouse model using mesothelioma AB1 cell line that stably expresses HIV-1 Gag fused with firefly luciferase. This AB1-Gag-Luc cell line shows identical growth kinetics in mice compared to parental AB1 cell. We then investigate a novel DNA vaccine to particularly stimulate antigen specific CD8+ T cell responses, which involves the fusion of soluble PD-1 protein with a HIV Gag to target dendritic cell effectively. As compared with traditional DNA vaccination, preventive use of the new vaccine elicited immunity that significantly reduced the tumor growth post AB1-Gag-Luc challenge due to Gag-specific cytotoxocity activity detected in both CD4+ and CD8+ T cell subsets. Moreover, therapeutic use of the new vaccine significantly reduced tumor growth and improved tumor-free survival in tumor bearing BALB/c mice. Importantly, adoptive transfer and T cell depletion experiments indicated that Gag-specific CD8+ T cells was more effective than CD4+ T cells in suppression of AB1-Gag-Luc cells in SCID and BALB/c mice, respectively. Our findings demonstrated that high level of antigen specific CD8+ cytotoxic T lymphocyte is essential for eliminating mesothelioma.
Involvement of IgG derived from cancer in tumor immune escape (P2147)
Authors: Qiu Xiaoyan , Shao Wenwei , Xiao Lin , Li Guohui , Huang Jing , Fu Ning 
Published: January 2023

Abstract
As we known that IgG have served as prototypical effector molecules of immune defense. However, monomeric IgG, such as the IVIG purified from the serum of thousands of healthy donors, has been demonstrated as an immune inhibitor at high doses as a commonly administered for the treatment of a number of autoimmune diseases. Igs has long been considered to be only produced by B cells, however, by a series of experimental evidences from ours and others, it has been found that other types of non-hematopoietic cells, especially cancer cells could also produce IgG, and the IgG is involved in the cell survival and carcinogenesis. In this study, we unexpectedly found that like the IVIG, epithelial cancer-derived IgG, but not the normal IgG, also showed strong immune inhibitory effect to CD4+ or CD8+ T lymphocytes at low dose. More importantly, the inhibitory effect of cancer-derived IgG was stronger than IVIG. Subsequently, we have analyzed the mechanism of the immune inhibition. Our results suggested that cancer-derived IgG can not directly inhibit the activation and proliferation of CD4+ or CD8+ T cells, their immune inhibitory effect should be dependent on myeloid cells, at least partly, dependent on the monocytes. In addition, we found that the immune inhibitory effect of cancer-derived IgG was not dependent on the Treg. Although the mechanism is remain unclear, we believe that the IgG is so far unknown arms of tumor cells to against the immune system for their immune escape.
Exosome from EBV-positive cell reduces vitamin D receptor expression on multiple myeloma (P2151)
Authors: Kim Hae jin , Kim Ja-young , Choi Yunock , Park Ga Bin , Kim Seonghan , Kim Bomi , Hur Dae Young , Kim Yeong Seok 
Published: January 2023

Abstract
Epstein-Barr Virus (EBV) is causative agent of cancer, and most people in the world are infected with EBV. EBV is deeply associated B cell lymphoma, nasopharyngeal carcinoma and gastric carcinoma. Some reported that EBV is linked to multiple myeloma. The therapy of multiple myeloma has been reported that it has effect on several anticancer drug and vitamin D. In this study, we studied whether EBV-infected cells or EBV itself modulate vitamin D receptor on multiple myeloma and resulting drug resistance. We add B95-8 cell supernatant including EBV particles to a multiple myeloma cell line NCI-H929 and we found that VDR mRNA and protein were decreased. However, there was no mRNA related with EBV genes. Experiments for cell proliferation and apoptosis showed that NCI-H929 have a resistance to vitamin D toxicity after adding with B95-8 cell supernatant. We also found that vitamin D receptor expression was decreased in NCI-H929 when we treated the exosome from EBV-infected B cell lymphoma or B95-8. As a result, exosomal components in EBV-positive cells may modulate susceptibility of vitamin D treatment on multiple myeloma. It can present the theoretical basis for vitamin D resistance appeared in multiple myeloma caused by the EBV-infected cells.
Myd88 signaling blockade induces antitumor effects by skewing the immunosuppressive function of MDSCs (P2155)
Authors: Ko Hyun-jeong , Lee Bora , Hong Eun-Hye 
Published: January 2023

Abstract
Myd88 is an important adaptor molecule for the activation of NADPH oxidase and arginase-1, which are responsible for the suppressive function of myeloid-derived suppressor cells (MDSCs). When wild-type and Myd88-/- mice were s.c. injected with CT26 colon cancer cells expressing human Her-2/neu, tumor growth was retarded in Myd88-/- mice than in wild-type mice. Although the generation of CD11b+Gr-1+ MDSCs was less in Myd88-/- mice than in wild-type mice, Myd88-/- mice having tumor masses still had significant quantities of MDSCs, suggesting that MDSC generation might be independent of Myd88 signaling. However, MDSCs obtained from tumor-bearing Myd88-/- mice failed to suppress antigen-specific proliferation of CD8+ T cells and CD4+ T cells, whereas MDSCs from wild-type mice significantly suppressed both types of T cells. Consistent with this, we found that the levels of costimulatory molecules and MHC class II were significantly increased in MDSCs obtained from Myd88-/- mice compared to wild-type mice after tumor challenge. Finally, the blockade of Myd88 signaling by treatment with Myd88 inhibitory peptide, during later tumor stages, significantly inhibited the growth of immunogenic tumors. Overall, these data suggest that signaling through the Myd88 adaptor molecule is critical for the direct suppressive function of MDSCs, and approaches to block Myd88-mediated signaling in MDSCs might be effective to inhibit the immunosuppressive function of MDSCs.
Eicosapentaenoic acid induces apoptosis in human pancreatic cancer cells: Role of ROS accumulation, caspase 8 activation, and autophagy induction (P2161)
Authors: Fukui Masayuki , Umemura Masayuki , Matsuzaki Goro 
Published: January 2023

Abstract
In a recent study, we showed that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), two common omega-3 fatty acids, can cause ROS accumulation and subsequently induce caspase-8-dependent apoptosis in human breast cancer cells in vitro and in vivo. In this study, we showed that the pancreas has a unique ability to accumulate EPA at a level markedly higher than several other tissues analyzed. Based on this finding, we sought to further investigate the anticancer actions of EPA and its analog DHA in human pancreatic cancer cells using both in vitro and in vivo models. EPA and DHA were found to induce ROS accumulation and caspase-8-dependent cell death in human pancreatic cancer cells (MIA-PaCa-2 and Capan-2) in vitro. Feeding animals with a diet supplemented with 5% fish oil, which contains high levels of EPA and DHA, also strongly suppresses the growth of MIA-PaCa-2 human pancreatic cancer xenografts in athymic nude mice, by inducing oxidative stress and cell death. In addition, we showed that EPA can concomitantly induce autophagy in these cancer cells, and the induction of autophagy diminishes its ability to induce apoptotic cell death. It is therefore suggested that combination of EPA with an autophagy inhibitor may be a useful strategy in increasing the therapeutic effectiveness in pancreatic cancer.
Integrins and chemokine receptors control maturation and duration of the cytotoxic immune synapse between CTL and tumor cells (P2171)
Authors: Mami-Chouaib Fathia , Boutet Marie , Le Floc'h Audrey , Franciszkiewicz Katarzyna 
Published: January 2023

Abstract
Cytotoxic T lymphocytes (CTL) exert their lytic activity through the polarized release of cytotoxic granules at the immune synapse (IS) formed with specific target cells. Integrins and their cognate ligands on target cells play a major role in T-cell receptor (TCR)-mediated functions. We show here that cytotoxicity towards epithelial cancer cells requires, along with TCR engagement, the interaction of either CD103 with E-cadherin or LFA-1 with ICAM-1 thereby enhancing the strength of the T-cell/target cell adhesion. Integrin-dependent mature cytotoxic IS (mcIS) displays a cohesive ultrastructure characterized by polarized degranulation and chemokine release associated with target cell killing and chemokine receptor induction on effector cells. Our results provide new insights into molecular mechanisms regulating antitumor CTL responses and the role of integrins and chemokine receptors on the formation and duration of the cIS.
BTLA: new biomarker for a highly proliferative CD8+ TIL subset associated with melanoma regression during adoptive cell therapy (P2189)
Authors: Haymaker Cara , Wu Richard , Bernatchez Chantale , Hwu Patrick , Radvanyi Laszlo 
Published: January 2023

Abstract
Adoptive T cell therapy using tumor-infiltrating lymphocytes (TIL) expanded ex vivo with high-dose IL-2 is a promising approach for the treatment of metastatic melanoma. Recently, our lab demonstrated the importance of CD8+ T cells expressing B and T lymphocyte attentuator (BTLA) with a positive clinical response. This suggests that functional differences may exist between CD8+BTLA+ and CD8+BTLA- cells resulting in the differential therapeutic potency of TIL in treated patients. Here, we isolated BTLA+ and BTLA- CD8+ TIL from metastatic melanoma patients accrued in a Phase II clinical trial at MD Anderson and performed functional assays measuring proliferation, apoptosis, cytokine production, and CTL activity as well as differences in global gene expression profiles between the subsets using microarray analysis. Overall, BTLA appears to be a new and powerful biomarker distinguishing a less differentiated, more highly active and polyfunctional CD8+ T cell subset with high responsiveness to IL-2. As BTLA ligation by its binding partner HVEM (which is expressed on melanoma cells) results in a decreased proliferative responsiveness to anti-CD3 stimulation, paradoxically, BTLA signaling however may still serve as a negative co-inhibitory molecule. Our results also underscore that increased expression of T cell co-inhibitory molecules may not be necessarily markers of “exhaustion”, but markers of more highly-activated, responsive T cells susceptible to negative regulation.
Murine prostate tumors recruit and expand thymic-derived regulatory T cell populations (P2191)
Authors: Malchow Sven , Leventhal Daniel , Nishi Saki , Fischer Benjamin , Socci Nicholas , Savage Peter 
Published: January 2023

Abstract
For some human cancers, elevated densities of Foxp3+ regulatory T cells (Tregs) in the tumor tissue correlate with poor prognosis, suggesting that Tregs may play a functional role in cancer progression. Despite considerable interest in the modulation of tumor-associated Tregs for therapeutic benefit, little is known about the developmental origins of these cells and the nature of the antigens that they recognize. By a TCR sequencing approach of T cells isolated from tumors of mice with oncogene-driven prostate cancer (TRAMP), we identified an endogenous population of antigen-specific Tregs found recurrently enriched in the tumors. These Tregs were not reactive to a tumor-specific antigen, but instead recognized a prostate-associated antigen that is present in tumor-free mice. Transgenic T cells expressing this Treg-derived TCR underwent Treg development in the thymus, but inefficient development in the periphery, indicating a thymic origin of these cells. Taken together, our data support a model in which organ-specific Tregs reactive to peripheral tissue antigens develop as Tregs in the thymus and are co-opted by tumors arising within the associated organ.
T cells dominate the immune infiltrate in human pancreatic cancer. (P2195)
Authors: Pillarisetty Venu , Shibuya Kendall 
Published: January 2023

Abstract
The absence of an effective immune response to pancreatic cancer is thought to contribute to the poor prognosis of this devastating disease. Recent studies using murine models of pancreatic cancer suggest that regulatory cells within the tumor microenvironment prevent effector CD8 T cells from entering and eliminating tumors. In order to gain a detailed understanding of the immune response to the human disease, we performed flow cytometry to study fresh tumor and blood from patients undergoing surgical resection for pancreatic cancer. Within the dense immune tumor infiltrate, a majority of the cells expressed CD3 (68.2 +/- 13.5%). The distribution of CD4 and CD8 T cells was, on average, comparable to the blood. However, we found significantly elevated levels of inflammatory IL-17 producing CD4 Th17 cells regulatory and CD25+FoxP3+ T cells within the tumor. Although there was a higher percentage of Tregs among the CD4 T cells in the tumor than in the blood, we found that the CD4 and CD8 T cells within the tumor were as capable of producing the inflammatory cytokines IFN-gamma (CD8: tumor 73.2% +/- 17.2%, blood 60 +/- 26%; CD4: tumor 33.3% +/- 12.3%, blood 24.2% +/- 13.9%) and IL-17 (CD4: tumor 4.3% +/- 4.2%, blood 1.35% +/- 1.3%) as their counterparts in the blood. In order to determine the relationship between the T cells and cancer cells, we performed CD3 immunohistochemistry and determined that infiltrating CD3+ cells are typically in close proximity to cancer cells.
Levels of murine, but not human, CXCL13 are greatly elevated in a NOD-SCID xenograft model of AIDS-associated Burkitt lymphoma (P2203)
Authors: Martinez-Maza Otoniel , Magpantay Larry , Widney Daniel 
Published: January 2023

Abstract
In these studies, a novel mouse/human xenograft model of AIDS-associated Burkitt lymphoma (AIDS-BL) was created by injecting cells of the AIDS-BL cell line, 2F7, intraperitoneally into NOD-SCID mice. Mice developed tumors in the peritoneal cavity, with metastases to the spleen, thymus, and mesenteric lymph nodes. Expression of the chemokine receptor, CXCR5, was greatly elevated in vivo on BL tumor cells in this model, as shown by flow cytometry. The chemokine ligand for CXCR5 is CXCL13, and serum and ascites levels of murine, but not human, CXCL13 showed a striking elevation in tumor-bearing mice, with levels as high as 200,000 pg/ml in tumor ascites, as measured by ELISA. As shown by immunohistochemistry, tumors were extensively infiltrated with F4/80+ histiocyte-like cells, many of which also stained positively for murine CXCL13. Blocking CXCR5 on 2F7 cells with neutralizing antibodies prior to injection into the mice substantially delayed tumor formation. The marked elevations in tumor cell CXCR5 expression and in murine CXCL13 levels seen in the model may identify an important link between tumor-interacting histiocytes and tumor cells in AIDS-BL, and also confirm previous results suggesting that CXCL13 is a potential biomarker for AIDS-NHL. This mouse model may be useful for future studies on the interactions of the innate immune system and AIDS-BL tumor cells, as well as for the identification of other potential tumor biomarkers for AIDS-NHL.