bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies
Authors: Evans Elizabeth E. , Jonason Alan S. , Bussler Holm , Torno Sebold , Veeraraghavan Janaki , Reilly Christine , Doherty Michael A. , Seils Jennifer , Winter Laurie A. , Mallow Crystal , Kirk Renee , Howell Alan , Giralico Susan , Scrivens Maria , Klimatcheva Katya , Fisher Terrence L. , Bowers William J. , Paris Mark , Smith Ernest S. , Zauderer Maurice
Published: March 2024

Abstract
Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 (PLXNB1) are broadly expressed in murine and human tumors, and their expression has been shown to correlate with invasive disease in several human tumors. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the setting of cancer, SEMA4D–PLXNB1 interactions have been reported to affect vascular stabilization and transactivation of ERBB2, but effects on immune-cell trafficking in the tumor microenvironment (TME) have not been investigated. We describe a novel immunomodulatory function of SEMA4D, whereby strong expression of SEMA4D at the invasive margins of actively growing tumors influences the infiltration and distribution of leukocytes in the TME. Antibody neutralization of SEMA4D disrupts this gradient of expression, enhances recruitment of activated monocytes and lymphocytes into the tumor, and shifts the balance of cells and cytokines toward a proinflammatory and antitumor milieu within the TME. This orchestrated change in the tumor architecture was associated with durable tumor rejection in murine Colon26 and ERBB2+ mammary carcinoma models. The immunomodulatory activity of anti-SEMA4D antibody can be enhanced by combination with other immunotherapies, including immune checkpoint inhibition and chemotherapy. Strikingly, the combination of anti-SEMA4D antibody with antibody to CTLA-4 acts synergistically to promote complete tumor rejection and survival. Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the TME and inhibit tumor progression. Cancer Immunol Res; 3(6); 689–701. ©2015 AACR.
Data from Targeting CD20+ Aggressive B-cell Non–Hodgkin Lymphoma by Anti-CD20 CAR mRNA-Modified Expanded Natural Killer Cells In Vitro and in NSG Mice
Authors: Chu Yaya , Hochberg Jessica , Yahr Ashlin , Ayello Janet , van de Ven Carmella , Barth Matthew , Czuczman Myron , Cairo Mitchell S.
Published: March 2024

Abstract
The prognosis is very dismal for patients with relapsed CD20+ B-cell non-Hodgkin lymphoma (B-NHL). Facilitating the development of alternative novel therapeutic strategies is required to improve outcomes in patients with recurrent/refractory CD20+ B-NHL. In this study, we investigated functional activities of anti-CD20 CAR-modified, expanded peripheral blood NK cells (exPBNK) following mRNA nucleofection against CD20+ B-NHL in vitro and in vivo. CAR+ exPBNK had significantly enhanced in vitro cytotoxicity, compared with CAR− exPBNK against CD20+ Ramos (P < 0.05), Daudi, Raji, and two rituximab-resistant cell lines, Raji-2R and Raji-4RH (P < 0.001). As expected, there was no significant difference against CD20− RS4;11 and Jurkat cells. CD107a degranulation and intracellular IFNγ production were also enhanced in CAR+ exPBNK in response to CD20+ B-NHL–specific stimulation. In Raji-Luc and Raji-2R-Luc xenografted NOD/SCID/γ-chain−/− (NSG) mice, the luciferase signals measured in the CAR+ exPBNK-treated group were significantly reduced, compared with the signals measured in the untreated mice and in mice treated with the CAR− exPBNK. Furthermore, the CAR exPBNK-treated mice had significantly extended survival time (P < 0.001) and reduced tumor size, compared with those of the untreated and the CAR− exPBNK-treated mice (P < 0.05). These preclinical data suggest that ex vivo–exPBNK modified with anti-CD20 CAR may have therapeutic potential for treating patients with poor-risk CD20+ hematologic malignancies. Cancer Immunol Res; 3(4); 333–44. ©2014 AACR.
Data from Interleukin-12 from CD103+ Batf3-Dependent Dendritic Cells Required for NK-Cell Suppression of Metastasis
Authors: Mittal Deepak , Vijayan Dipti , Putz Eva M. , Aguilera Amelia R. , Markey Kate A. , Straube Jasmin , Kazakoff Stephen , Nutt Stephen L. , Takeda Kazuyoshi , Hill Geoffrey R. , Waddell Nicola , Smyth Mark J.
Published: March 2024

Abstract
Several host factors may affect the spread of cancer to distant organs; however, the intrinsic role of dendritic cells (DC) in controlling metastasis is poorly described. Here, we show in several tumor models that although the growth of primary tumors in Batf3-deficient mice, which lack cross-presenting DCs, was not different from primary tumors in wild-type (WT) control mice, Batf3-deficient mice had increased experimental and spontaneous metastasis and poorer survival. The increased metastasis was independent of CD4+ and CD8+ T lymphocytes, but required NK cells and IFNγ. Chimeric mice in which Batf3-dependent DCs uniformly lacked the capacity to produce IL12 had metastatic burdens similar to the Batf3-deficient mice, suggesting that Batf3+ DCs were the only cell type whose IL12 production was critical for controlling metastasis. We found that IL12-YFP reporter mice, whose lungs were injected with B16F10 melanoma, had increased numbers of IL12-expressing CD103+ DCs with enhanced CD86 expression. Bone-marrow–derived DCs from WT, but not Batf3-deficient, mice activated NK cells to produce IFNγ in an IL12-dependent manner and therapeutic injection of recombinant mouse IL12 decreased metastasis in both WT and Batf3-deficient mice. Analysis of TCGA datasets revealed an association between high expression of BATF3 and IRF8 and improved survival of breast cancer patients; BATF3 expression also significantly correlated with NK-cell receptor genes, IL12, and IFNG. Collectively, our findings show that IL12 from CD103+ DCs is critical for NK cell–mediated control of tumor metastasis. Cancer Immunol Res; 5(12); 1098–108. ©2017 AACR.
Data from Induction of NKG2D Ligands on Solid Tumors Requires Tumor-Specific CD8+ T Cells and Histone Acetyltransferases
Authors: Hu Jiemiao , Bernatchez Chantale , Zhang Liangfang , Xia Xueqing , Kleinerman Eugenie S. , Hung Mien-Chie , Hwu Patrick , Li Shulin
Published: March 2024

Abstract
NKG2D-mediated immune surveillance is crucial for inhibiting tumor growth and metastases. Malignant tumor cells often downregulate NKG2D ligands to escape from immune surveillance. High-profile studies have shown that restoring NKG2D ligand expression via genetic engineering inhibits tumor formation and progression. However, no effective in vivo approaches are available to restore these ligands across different types of solid tumors because the classic stress signal–dependent induction of this ligand in vitro is transient and has rarely been duplicated in solid tumors in vivo. We found that coadministration of an immune stimulatory signal (IL12) and chemotherapy (doxorubicin) restored the NKG2D ligand Rae-1 in multiple tumor types, including a human tumor model. The restored expression of NKG2D ligands was associated with tumor cell death and delay of tumor progression in vivo. Induction of tumor-specific NKG2D ligands required the engagement of CD8+ T cells and was regulated by the histone acetyltransferases GCN5 and PCAF. The tumor-specific restoration of NKG2D ligands in a variety of tumor models, including a human tumor model, resulted in NKG2D-dependent tumor regression and extended survival time. The elucidation of a CD8+ T cell–dependent mechanism suggests that activated NKG2D+CD8+ T-cell therapy alone may be able to restore the NKG2D ligand in tumors. Cancer Immunol Res; 5(4); 300–11. ©2017 AACR.
Data from Tumor Lymphatic Function Regulates Tumor Inflammatory and Immunosuppressive Microenvironments
Authors: Kataru Raghu P. , Ly Catherine L. , Shin Jinyeon , Park Hyeung Ju , Baik Jung Eun , Rehal Sonia , Ortega Sagrario , Lyden David , Mehrara Babak J.
Published: March 2024

Abstract
Proliferation of aberrant, dysfunctional lymphatic vessels around solid tumors is a common histologic finding. Studies have shown that abnormalities in lymphatic function result in accumulation of inflammatory cells with an immunosuppressive profile. We tested the hypothesis that dysfunctional lymphatic vessels surrounding solid tumors regulate changes in the tumor microenvironment and tumor-specific immune responses. Using subcutaneously implanted mouse melanoma and breast cancer tumors in a lymphatic endothelial cell–specific diphtheria toxin receptor transgenic mouse, we found that local ablation of lymphatic vessels increased peritumoral edema, as compared with controls. Comparative analysis of the peritumoral fluid demonstrated increases in the number of macrophages, CD4+ inflammatory cells, F4/80+/Gr-1+ (myeloid-derived suppressor cells), CD4+/Foxp3+ (Tregs) immunosuppressive cells, and expression of inflammatory cytokines such as TNFα, IFNγ, and IL1β following lymphatic ablation. Tumors grown in lymphatic ablated mice exhibited reduced intratumoral accumulation of cytotoxic T cells and increased tumor PD-L1 expression, causing rapid tumor growth, compared with tumors grown in nonlymphatic-ablated mice. Our study suggests that lymphatic dysfunction plays a role in regulating tumor microenvironments and may be therapeutically targeted in combination with immunotherapy to prevent tumor growth and progression.
Data from Safety and Efficacy of Re-treating with Immunotherapy after Immune-Related Adverse Events in Patients with NSCLC
Authors: Santini Fernando C. , Rizvi Hira , Plodkowski Andrew J. , Ni Andy , Lacouture Mario E. , Gambarin-Gelwan Maya , Wilkins Olivia , Panora Elizabeth , Halpenny Darragh F. , Long Niamh M. , Kris Mark G. , Rudin Charles M. , Chaft Jamie E. , Hellmann Matthew D.
Published: March 2024

Abstract
Considering retreatment following recovery from an immune-related adverse event (irAE) is a common clinical scenario, but the safety and benefit of retreatment is unknown. We identified patients with advanced non–small cell lung cancer (NSCLC) treated with anti-PD-(L)1 who had treatment held due to irAEs and divided them into two groups: those retreated with anti-PD-(L)1 (retreatment cohort) or those who had treatment stopped (discontinuation cohort). Out of 482 NSCLC patients treated with anti-PD-(L)1, 68 (14%) developed a serious irAE requiring treatment interruption. Of these, 38 (56%) were retreated and 30 (44%) had treatment discontinued. In the retreatment cohort, 18 (48%) patients had no subsequent irAEs, 10 (26%) had recurrence of the initial irAE, and 10 (26%) had a new irAE. Most recurrent/new irAEs were mild (58% grade 1–2) and manageable (84% resolved or improved to grade 1). Two treatment-related deaths occurred. Recurrent/new irAEs were more likely if the initial irAE required hospitalization, but the initial grade and time to retreatment did not influence risk. Among those with no observed partial responses prior to the irAE, progression-free survival (PFS) and overall survival (OS) were longer in the retreatment cohort. Conversely, for those with objective responses prior to the irAE, PFS and OS were similar in the retreatment and discontinuation cohorts. Among patients with early objective responses prior to a serious irAE, outcomes were similar, whether or not they were retreated. Together, data suggest that benefit may occur with retreatment in patients with irAEs who had no treatment response prior to irAE onset. Cancer Immunol Res; 6(9); 1093–9. ©2018 AACR.
Data from Early-Life Microbiota Exposure Restricts Myeloid-Derived Suppressor Cell–Driven Colonic Tumorigenesis
Authors: Harusato Akihito , Viennois Emilie , Etienne-Mesmin Lucie , Matsuyama Shingo , Abo Hirohito , Osuka Satoru , Lukacs Nicholas W. , Naito Yuji , Itoh Yoshito , Li Jian-Dong , Merlin Didier , Gewirtz Andrew T. , Denning Timothy L.
Published: March 2024

Abstract
Gut microbiota and their metabolites are instrumental in regulating homeostasis at intestinal and extraintestinal sites. However, the complex effects of prenatal and early postnatal microbial exposure on adult health and disease outcomes remain incompletely understood. Here, we showed that mice raised under germ-free conditions until weaning and then transferred to specific pathogen-free (SPF) conditions harbored altered microbiota composition, augmented inflammatory cytokine and chemokine expression, and were hyper-susceptible to colitis-associated tumorigenesis later in adulthood. Increased number and size of colon tumors and intestinal epithelial cell proliferation in recolonized germ-free mice were associated with augmented intratumoral CXCL1, CXCL2, and CXCL5 expression and granulocytic myeloid-derived suppressor cell (G-MDSC) accumulation. Consistent with these findings, CXCR2 neutralization in recolonized germ-free mice completely reversed the exacerbated susceptibility to colitis-associated tumorigenesis. Collectively, our findings highlight a crucial role for early-life microbial exposure in establishing intestinal homeostasis that restrains colon cancer in adulthood.
Data from Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic Antitumor Immunity
Authors: Ager Casey R. , Reilley Matthew J. , Nicholas Courtney , Bartkowiak Todd , Jaiswal Ashvin R. , Curran Michael A.
Published: March 2024

Abstract
Coordinated manipulation of independent immune regulatory pathways in the tumor microenvironment—including blockade of T-cell checkpoint receptors and reversal of suppressive myeloid programs—can render aggressive cancers susceptible to immune rejection. Elevated toxicity associated with combination immunotherapy, however, prevents translation of the most efficacious regimens. We evaluated T-cell checkpoint–modulating antibodies targeting CTLA-4, PD-1, and 4-1BB together with myeloid agonists targeting either STING or Flt3 in the TRAMP-C2 model of prostate cancer to determine whether low-dose intratumoral delivery of these agents could elicit systemic control of multifocal disease. Intratumoral administration of the STING agonist cyclic di-GMP (CDG) or Flt3 Ligand (Flt3L) augmented the therapeutic effect of systemic triple checkpoint modulation and promoted the cure of 75% of mice with bilateral TRAMP-C2; however, when all agents were administered locally, only CDG mobilized abscopal immunity. Combination efficacy correlated with globally enhanced ratios of CD8+ T cells to regulatory T cells (Treg), macrophages, and myeloid-derived suppressor cells, and downregulation of the M2 marker CD206 on tumor-associated macrophages. Flt3L improved CD8+ T-cell and dendritic cell infiltration of tumors, but was diminished in efficacy by concomitant Treg expansion. Although intratumoral CDG/checkpoint therapy invokes substantial ulceration at the injection site, reduced CDG dosing can preserve tissue integrity without sacrificing therapeutic benefit. For high-order combinations of T-cell checkpoint antibodies and local myeloid agonists, systemic antibody administration provides the greatest efficacy; however, local administration of CDG and antibody provides substantial systemic benefit while minimizing the potential for immune-related adverse events. Cancer Immunol Res; 5(8); 676–84. ©2017 AACR.
Data from Concurrent PD-1 Blockade Negates the Effects of OX40 Agonist Antibody in Combination Immunotherapy through Inducing T-cell Apoptosis
Authors: Shrimali Rajeev K. , Ahmad Shamim , Verma Vivek , Zeng Peng , Ananth Sudha , Gaur Pankaj , Gittelman Rachel M. , Yusko Erik , Sanders Catherine , Robins Harlan , Hammond Scott A. , Janik John E. , Mkrtichyan Mikayel , Gupta Seema , Khleif Samir N.
Published: March 2024

Abstract
Combination therapies that depend on checkpoint inhibitor antibodies (Abs) such as for PD-1 or its ligand (PD-L1) together with immune stimulatory agonist Abs like anti-OX40 are being tested in the clinic to achieve improved antitumor effects. Here, we studied the potential therapeutic and immune effects of one such combination: Ab to PD-1 with agonist Ab to OX40/vaccine. We tested the antitumor effects of different treatment sequencing of this combination. We report that simultaneous addition of anti–PD-1 to anti-OX40 negated the antitumor effects of OX40 Ab. Antigen-specific CD8+ T-cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival reduced. Although we observed an increase in IFNγ-producing E7-specifc CD8+ T cells in the spleens of mice treated with the combination of PD-1 blockade with anti-OX40/vaccine, these cells underwent apoptosis both in the periphery and the tumor. These results indicate that anti–PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist Ab. These findings have important implications on the design of combination immunotherapy for cancer, demonstrating the need to test treatment combination and sequencing before moving to the clinic. Cancer Immunol Res; 5(9); 755–66. ©2017 AACR.
Data from IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells
Authors: Clancy-Thompson Eleanor , Ali Lestat , Bruck Patrick T. , Exley Mark A. , Blumberg Richard S. , Dranoff Glenn , Dougan Michael , Dougan Stephanie K.
Published: March 2024

Abstract
Inhibitor of apoptosis protein (IAP) antagonists are in clinical trials for a variety of cancers, and mouse models show synergism between IAP antagonists and anti–PD-1 immunotherapy. Although IAP antagonists affect the intrinsic signaling of tumor cells, their most pronounced effects are on immune cells and the generation of antitumor immunity. Here, we examined the effects of IAP antagonism on T-cell development using mouse fetal thymic organ culture and observed a selective loss of iNKT cells, an effector cell type of potential importance for cancer immunotherapy. Thymic iNKT-cell development probably failed due to increased strength of TCR signal leading to negative selection, given that mature iNKT cells treated with IAP antagonists were not depleted, but had enhanced cytokine production in both mouse and human ex vivo cultures. Consistent with this, mature mouse primary iNKT cells and iNKT hybridomas increased production of effector cytokines in the presence of IAP antagonists. In vivo administration of IAP antagonists and α-GalCer resulted in increased IFNγ and IL-2 production from iNKT cells and decreased tumor burden in a mouse model of melanoma lung metastasis. Human iNKT cells also proliferated and increased IFNγ production dramatically in the presence of IAP antagonists, demonstrating the utility of these compounds in adoptive therapy of iNKT cells. Cancer Immunol Res; 6(1); 25–35. ©2017 AACR.
Data from Autologous Lymphocyte Infusion Supports Tumor Antigen Vaccine–Induced Immunity in Autologous Stem Cell Transplant for Multiple Myeloma
Authors: Cohen Adam D. , Lendvai Nikoletta , Nataraj Sarah , Imai Naoko , Jungbluth Achim A. , Tsakos Ioanna , Rahman Adeeb , Mei Anna Huo-Chang , Singh Herman , Zarychta Katarzyna , Kim-Schulze Seunghee , Park Andrew , Venhaus Ralph , Alpaugh Katherine , Gnjatic Sacha , Cho Hearn J.
Published: March 2024

Abstract
Autologous stem cell transplant (autoSCT), the standard consolidation therapy for multiple myeloma, improves disease-free survival, but is not curative. This could be an ideal setting for immunologic therapy. However, the immune milieu is impaired after autoSCT. We hypothesized that autologous lymphocyte infusion would restore immune competence, allowing immunotherapies such as cancer vaccines to elicit tumor antigen–specific immunity in the setting of autoSCT. In this pilot study (NCT01380145), we investigated safety, immunologic, and clinical outcomes of autologous lymphocyte infusion combined with peri-autoSCT immunotherapy with recombinant MAGE-A3 (a multiple myeloma–associated antigen) and adjuvant. Thirteen patients with multiple myeloma undergoing autoSCT were enrolled. Autologous lymphocyte infusion and MAGE vaccination were well tolerated. Combination immunotherapy resulted in high-titer humoral immunity and robust, antigen-specific CD4+ T-cell responses in all subjects, and the responses persisted at least one year post-autoSCT. CD4+ T cells were polyfunctional and Th1-biased. CD8+ T-cell responses were elicited in 3 of 13 subjects. These cells recognized naturally processed MAGE-A3 antigen. Median progression-free survival was 27 months, and median overall survival was not reached, suggesting no differences from standard-of-care. In 4 of 8 subjects tested, MAGE-A protein expression was not detected by IHC in multiple myeloma cells at relapse, suggesting therapy-induced immunologic selection against antigen-expressing clones. These results demonstrated that autologous lymphocyte infusion augmentation of autoSCT confers a favorable milieu for immunotherapies such as tumor vaccines. This strategy does not require ex vivo manipulation of autologous lymphocyte products and is an applicable platform for further investigation into combination immunotherapies to treat multiple myeloma.
Data from Cripto-1 Plasmid DNA Vaccination Targets Metastasis and Cancer Stem Cells in Murine Mammary Carcinoma
Authors: Witt Kristina , Ligtenberg Maarten A. , Conti Laura , Lanzardo Stefania , Ruiu Roberto , Wallmann Tatjana , Tufvesson-Stiller Helena , Chambers Benedict J. , Rolny Charlotte , Lladser Alvaro , Lundqvist Andreas , Cavallo Federica , Kiessling Rolf
Published: March 2024

Abstract
Metastatic breast cancer is a fatal disease that responds poorly to treatment. Cancer vaccines targeting antigens expressed by metastatic breast cancer cells and cancer stem cells could function as anticancer therapies. Cripto-1 is an oncofetal protein overexpressed in invasive breast cancer and cancer-initiating cells. In this study, we explored the potential of a Cripto-1–encoding DNA vaccine to target breast cancer in preclinical mouse models. BALB/c mice and BALB-neuT mice were treated with a DNA vaccine encoding mouse Cripto-1 (mCr-1). BALB/c mice were challenged with murine breast cancer 4T1 cells or TUBO spheres; BALB-neuT mice spontaneously developed breast cancer. Tumor growth was followed in all mouse models and lung metastases were evaluated. In vitro assays were performed to identify the immune response elicited by vaccination. Vaccination against mCr-1 reduced primary tumor growth in the 4T1 metastatic breast cancer model and reduced lung metastatic burden. In BALB-neuT mice, because the primary tumors are Cripto-1 negative, vaccination against mCr-1 did not affect primary tumors but did reduce lung metastatic burden. Spheroid-cultured TUBO cells, derived from a BALB/neuT primary tumor, develop a cancer stem cell–like phenotype and express mCr-1. We observed reduced tumor growth in vaccinated mice after challenge with TUBO spheres. Our data indicate that vaccination against Cripto-1 results in a protective immune response against mCr-1 expressing and metastasizing cells. Targeting Cripto-1 by vaccination holds promise as an immunotherapy for treatment of metastatic breast cancer. Cancer Immunol Res; 6(11); 1417–25. ©2018 AACR.
Data from IL13-Mediated Dectin-1 and Mannose Receptor Overexpression Promotes Macrophage Antitumor Activities through Recognition of Sialylated Tumor Cells
Authors: Alaeddine Mohamad , Prat Mélissa , Poinsot Véréna , Gouazé-Andersson Valérie , Authier Hélène , Meunier Etienne , Lefèvre Lise , Alric Camille , Dardenne Christophe , Bernad José , Alric Laurent , Segui Bruno , Balard Patricia , Couderc François , Couderc Bettina , Pipy Bernard , Coste Agnès
Published: March 2024

Abstract
Macrophage-mediated cytotoxicity is controlled by surface receptor expression and activation. Despite the numerous studies documenting the role of macrophage C-type lectin receptors (CLR) in pathogen elimination, little is known about their contribution to antitumor responses. Here, we report that IL13 inhibits T-cell lymphoma and ovarian adenocarcinoma development in tumor-bearing mice through the conversion of tumor-supporting macrophages to cytotoxic effectors, characterized by a CLR signature composed of dectin-1 and mannose receptor (MR). We show that dectin-1 and MR are critical for the recognition of tumor cells through sialic acid–specific glycan structure on their surface and for the subsequent activation of macrophage tumoricidal response. Finally, we validated that IL13 antitumor effect mediated by dectin-1 and MR overexpression on macrophages can extend to various types of human tumors. Therefore, these results identify these CLRs as potential targets to promote macrophage antitumor response and represent an attractive approach to elicit tumor-associated macrophage tumoricidal properties.
Data from Disruption of IFN-I Signaling Promotes HER2/Neu Tumor Progression and Breast Cancer Stem Cells
Authors: Castiello Luciano , Sestili Paola , Schiavoni Giovanna , Dattilo Rosanna , Monque Domenica M. , Ciaffoni Fiorella , Iezzi Manuela , Lamolinara Alessia , Sistigu Antonella , Moschella Federica , Pacca Anna Maria , Macchia Daniele , Ferrantini Maria , Zeuner Ann , Biffoni Mauro , Proietti Enrico , Belardelli Filippo , Aricò Eleonora
Published: March 2024

Abstract
Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neu+/− mice (neuT mice), IFNAR1−/− neu+/− mice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1). An increased number of BCSCs were observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay, and tumorigenic capacity. In vitro exposure of neuT+ mammospheres and cell lines to antibodies to IFN-I resulted in increased frequency of ALDH+ cells, suggesting that IFN-I controls stemness in tumor cells. Altogether, these results reveal a role of IFN-I in neuT-driven spontaneous carcinogenesis through intrinsic control of BCSCs. Cancer Immunol Res; 6(6); 658–70. ©2018 AACR.
Data from Primary T Cells from Cutaneous T-cell Lymphoma Skin Explants Display an Exhausted Immune Checkpoint Profile
Authors: Querfeld Christiane , Leung Samantha , Myskowski Patricia L. , Curran Shane A. , Goldman Debra A. , Heller Glenn , Wu Xiwei , Kil Sung Hee , Sharma Sneh , Finn Kathleen J. , Horwitz Steven , Moskowitz Alison , Mehrara Babak , Rosen Steven T. , Halpern Allan C. , Young James W.
Published: March 2024

Abstract
Cutaneous T-cell lymphoma (CTCL) develops from clonally expanded CD4+ T cells in a background of chronic inflammation. Although dendritic cells (DCs) stimulate T cells and are present in skin, cutaneous T cells in CTCL do not respond with effective antitumor immunity. We evaluated primary T-cell and DC émigrés from epidermal and dermal explant cultures of skin biopsies from CTCL patients (n = 37) and healthy donors (n = 5). Compared with healthy skin, CD4+ CTCL populations contained more T cells expressing PD-1, CTLA-4, and LAG-3. CD8+ CTCL populations contained more T cells expressing CTLA-4 and LAG-3. CTCL populations also contained more T cells expressing the inducible T-cell costimulator (ICOS), a marker of T-cell activation. DC émigrés from healthy or CTCL skin biopsies expressed PD-L1, indicating that maturation during migration resulted in PD-L1 expression irrespective of disease. Most T cells did not express PD-L1. Using skin samples from 49 additional CTCL patients for an unsupervised analysis of genome-wide mRNA expression profiles corroborated that advanced T3/T4-stage samples expressed more checkpoint inhibition mRNA compared with T1/T2 stage patients or healthy controls. Exhaustion of activated T cells is therefore a hallmark of both CD4+ and CD8+ T cells isolated from the lesional skin of patients with CTCL, with increasing expression as the disease progresses. These results justify identification of antigens driving T-cell exhaustion and the evaluation of immune checkpoint inhibition to reverse T-cell exhaustion earlier in the treatment of CTCL. Cancer Immunol Res; 6(8); 900–9. ©2018 AACR.
Data from Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells
Authors: Rudqvist Nils-Petter , Pilones Karsten A. , Lhuillier Claire , Wennerberg Erik , Sidhom John-William , Emerson Ryan O. , Robins Harlan S. , Schneck Jonathan , Formenti Silvia C. , Demaria Sandra
Published: March 2024

Abstract
Immune checkpoint inhibitors activate T cells to reject tumors. Unique tumor mutations are key T-cell targets, but a comprehensive understanding of the nature of a successful antitumor T-cell response is lacking. To investigate the T-cell receptor (TCR) repertoire associated with treatment success versus failure, we used a well-characterized mouse carcinoma that is rejected by CD8 T cells in mice treated with radiotherapy (RT) and anti–CTLA-4 in combination, but not as monotherapy, and comprehensively analyzed tumor-infiltrating lymphocytes (TILs) by high-throughput sequencing of the TCRΒ CDR3 region. The combined treatment increased TIL density and CD8/CD4 ratio. Assessment of the frequency of T-cell clones indicated that anti–CTLA-4 resulted in fewer clones and a more oligoclonal repertoire compared with untreated tumors. In contrast, RT increased the CD8/CD4 ratio and broadened the TCR repertoire, and when used in combination with anti–CTLA-4, these selected T-cell clones proliferated. Hierarchical clustering of CDR3 sequences showed a treatment-specific clustering of TCRs that were shared by different mice. Abundant clonotypes were commonly shared between animals and yet treatment-specific. Analysis of amino-acid sequence similarities revealed a significant increase in the number and richness of dominant CDR3 motifs in tumors treated with RT + anti–CTLA-4 compared with control. The repertoire of TCRs reactive with a single tumor antigen recognized by CD8+ T cells was heterogeneous but highly clonal, irrespective of treatment. Overall, data support a model whereby a diverse TCR repertoire is required to achieve tumor rejection and may underlie the synergy between RT and CTLA-4 blockade. Cancer Immunol Res; 6(2); 139–50. ©2017 AACR.
Data from CCL20 Expression by Tumor-Associated Macrophages Predicts Progression of Human Primary Cutaneous Melanoma
Authors: Samaniego Rafael , Gutiérrez-González Alejandra , Gutiérrez-Seijo Alba , Sánchez-Gregorio Sandra , García-Giménez Jorge , Mercader Enrique , Márquez-Rodas Iván , Avilés José Antonio , Relloso Miguel , Sánchez-Mateos Paloma
Published: March 2024

Abstract
The chemokine axis CCR6/CCL20 is involved in cancer progression in a variety of tumors. Here, we show that CCR6 is expressed by melanoma cells. The CCR6 ligand, CCL20, induces migration and proliferation in vitro, and enhances tumor growth and metastasis in vivo. Confocal analysis of melanoma tissues showed that CCR6 is expressed by tumor cells, whereas CCL20 is preferentially expressed by nontumoral cells in the stroma of certain tumors. Stromal CCL20, but not tumoral CCR6, predicted poor survival in a cohort of 40 primary melanoma patients. Tumor-associated macrophages (TAM), independently of their M1/M2 polarization profile, were identified as the main source of CCL20 in primary melanomas that developed metastasis. In addition to CCL20, TAMs expressed TNF and VEGF-A protumoral cytokines, suggesting that melanoma progression is supported by macrophages with a differential activation state. Our data highlight the synergistic interaction between melanoma tumor cells and prometastatic macrophages through a CCR6/CCL20 paracrine loop. Stromal levels of CCL20 in primary melanomas may be a clinically useful marker for assessing patient risk, making treatment decisions, and planning or analyzing clinical trials. Cancer Immunol Res; 6(3); 267–75. ©2018 AACR.
Differences between Myeloschisis and Myelomeningocele in Patients Undergoing Prenatal Repair of Open Spina Bifida
Authors: Müller José Miguel , Corral Sereño Edgardo , Jimenez Aura , Zapata Rodrigo , Echeverria Silvana , Jara Juan Pablo , Santibanez Alvaro , Lindsay Carolina , Anfossi Renatto
Published: March 2024

Introduction: Open spina bifida (OSB) manifests as myelomeningocele (MMC) or myeloschisis (MS). Both lesions theoretically leak cerebrospinal fluid (CSF) and produce different degrees of Chiari II malformation (CHMII). However, it is not entirely clear whether these forms of OSB have different clinical manifestations. This study aimed to evaluate the clinical and/or radiological differences between MS and MMC in patients who underwent prenatal OSB repair. Methods: A total of 71 prenatal repairs were performed with the open technique at the Public Hospital of Rancagua, Chile, between 2012 and 2022. We performed follow-up magnetic resonance imaging (MRI) of fetuses that qualified for prenatal OSB repair surgery. We examined the correlations between various anthropomorphic measurements and clinical and imaging variables, such as the type of lesion and dimensions such as ventricle atrium diameter, degree of severity of CHMII, need for CSF shunt at 12 months, and walking at 30 months. Results: This study included 71 fetuses with OSB for which 38 MRI examinations were analyzed; 61% (43/71) of lesions were MMC and 39% (28/71) were MS. Grade 3 (severe) Chiari II malformations were found in 80% (12/15) of MS and 43% (10/23) of MMC (p < 0.05). Fetuses with an atrial diameter less than 13.48 mm had a lower probability of requiring a CSF shunt at 12 months (p < 0.05). MMC was associated with a significantly higher frequency of clubfoot at birth (p < 0.05), whereas MS was significantly associated with more severe CHMII (p < 0.05). Although the correlations were not significant, we observed clear trends that more children with MS required shunts at 12 months and could walk at 30 months compared to children with MMC. Conclusions: MS and MMC are distinct subtypes of OSB. Further studies of larger cohorts that include biomolecular and histological analysis are required to better understand the differences between these lesions. The findings of this study may enable healthcare providers to better advise parents and prepare healthcare teams earlier for the management of patients undergoing prenatal repair of OSB.
Examining the Proteus Effect in the Context of Healthy Food Choices and Intentions to Eat Healthy: The Role of Avatar Body Size, Avatar Allocation Type, and Visual Perspective
Authors: van der Waal Nadine Elisa , Janssen Loes , Antheunis Marjolijn , van der Laan Laura Nynke
Published: March 2024

As avatars gain prominence in health-promoting applications, understanding how health-related avatar appearance characteristics could affect users’ behavior is crucial. Drawing upon the Proteus effect, avatars can positively and negatively affect health behaviors, depending on whether the avatar appearance is aligned with stereotypes about healthy or unhealthy behavior. Investigating avatar appearances is essential to understand potential negative health effects. Three experiments in a non-immersive virtual supermarket examined whether controlling an overweight avatar negatively affected (1) intentions to eat healthy and (2) food choice healthiness in the virtual supermarket, thereby investigating avatar allocation type (Study 1) and visual perspective (Study 2) as moderators. The studies employed 2 (Avatar body size: overweight vs. healthy weight) by 2 (Avatar allocation type: self-assigned vs. experimenter-assigned [Study 1]; Visual perspective: first-person vs. third-person [Studies 2 and 3]) between-subjects designs. None of the studies demonstrated the Proteus effect, and no moderating role of avatar allocation type was found (Study 1). Unexpectedly, controlling an overweight avatar resulted in stronger intentions to eat healthy from a third-person perspective only (Study 2), which led to the hypothesis that the overweight avatar functioned as a fear stimulus. To test this, a health message was added that highlighted obesity as a health risk (Study 3). The addition of this message did not affect intentions to eat healthy and food choice healthiness. The combination of fear appeal and self-perception theory as explanatory frameworks for behavioral responses to avatars opens avenues for new research, such as exploring specific conditions that trigger each effect.
Description of the female of Leptagrion jeromei Lencioni, Vilela & Furieri, 2021 (Odonata: Coenagrionidae) with taxonomic notes on the male
Authors: FARIAS ANTONIO BRUNO SILVA , SANTOS JEAN CARLOS
Published: March 2024

The female of Leptagrion jeromei Lencioni, Vilela & Furieri, 2021 is described, illustrated, and diagnosed based on a specimen collected in epiphytic bromeliads at the Federal University of Sergipe (♀ (B0545), BRAZIL, Federal University of Sergipe, São Cristóvão, -10.92707, -37.10100, 30 m asl, 6.x.2023, A.B.S. Farias & J.C. Santos leg.). Additionally, we provide information on its biology, ecology, and taxonomic notes, along with illustrations of the collected males.
Action of GABAB receptor on local network oscillation in somatosensory cortex of oral part: focusing on NMDA receptor
Authors: Kanayama Hiroyuki , Tominaga Takashi , Tominaga Yoko , Kato Nobuo , Yoshimura Hiroshi
Published: March 2024

The balance of activity between glutamatergic and GABAergic networks is particularly important for oscillatory neural activities in the brain. Here, we investigated the roles of GABAB receptors in network oscillation in the oral somatosensory cortex (OSC), focusing on NMDA receptors. Neural oscillation at the frequency of 8–10 Hz was elicited in rat brain slices after caffeine application. Oscillations comprised a non-NMDA receptor-dependent initial phase and a later NMDA receptor-dependent oscillatory phase, with the oscillator located in the upper layer of the OSC. Baclofen was applied to investigate the actions of GABAB receptors. The later NMDA receptor-dependent oscillatory phase completely disappeared, but the initial phase did not. These results suggest that GABAB receptors mainly act on NMDA receptor, in which metabotropic actions of GABAB receptors may contribute to the attenuation of NMDA receptor activities. A regulatory system for network oscillation involving GABAB receptors may be present in the OSC.
Risk stratification by systemic manifestations secondary to hemodynamic disorders of patients with severe tricuspid regurgitation
Authors: Ji Xing-Yu , Zhu Lei , Chen Fei , Lu Fang-Lin , Feng Yuan , Chen Mao , Xiong Tian-Yuan
Published: March 2024

Background

Tricuspid regurgitation (TR) is a prevalent disease that triggers systemic pathological changes including cardiac, respiratory, hepatic and digestive, hematopoietic, renal and skin issues. The burden of extra-cardiac manifestations has not been well described in TR patients and the clinical impact is unknown.

Methods

Patients with severe or more-than-severe TR during hospitalization, who did not have any previous cardiac procedures, hemodynamically significant congenital heart disease or concomitant severe aortic or mitral valve disease, were retrospectively analyzed. Pre-specified criteria and diagnosis of baseline characteristics were used to evaluate the presence of extra-cardiac manifestations secondary to TR after excluding comorbidities that may also lead to corresponding abnormalities. Extra-cardiac involvements encompass respiratory, hepatic and, digestive, renal, hematopoietic and dermatic system. Staging criteria are defined as no extra-cardiac system involvement in Stage 1, one in Stage 2, at least two extra-cardiac involvements in Stage 3 and any end-stage organ failure in Stage 4. A telephone follow-up was conducted to record the composite endpoint namely all-cause death or cardiac rehospitalization after the index hospitalization.

Results

A total of 258 patients were identified with a median age of 73 (interquartile range [IQR]: 62–83) years and 52.3% were female. Severe TR and more-than-severe TR patients accounted for 92.6% and 7.4% of the cohort. There were 20.5%, 27.5%, 37.6% and 14.3% of patients from Stage 1 to 4 respectively. The follow-up time was at a median of 251 (IQR: 183–324) days. TR Patients in Stage 3&4 were at an increased risk with borderline statistical significance to experience the composite endpoint compared to patients in Stage 1&2 (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.0 to 3.7, P = 0.049).

Conclusions

Approximately half of patients with at least severe TR presented with two or more extra-cardiac systemic manifestations, which may incur a 1.9-fold higher risk of all-cause death or cardiac rehospitalization than TR patients with one or less extra-cardiac involvement.
Modern physiological approach to inappropriate ICD shocks due to atrial fibrillation with very fast ventricular response. A case report
Authors: Pestrea Catalin , Enache Roxana , Cicala Ecaterina , Vatasescu Radu
Published: March 2024

Background

Fast-conducting atrial fibrillation misinterpreted as ventricular tachycardia is the leading cause for inappropriate shocks in patients with implantable cardiac defibrillators (ICD). These inappropriate shocks are associated with significant morbidity and mortality and cause great discomfort and stress.

Case presentation

We report the case of a patient with ischemic cardiomyopathy, permanent atrial fibrillation, and a single-chamber DF-1 ICD implanted for the primary prevention of sudden cardiac death, who presented for multiple inappropriate internal shocks due to very fast-conducting atrial fibrillation, which was mislabeled as ventricular fibrillation by the ICD. Since the patient was under maximal atrioventricular nodal blocking medical therapy (beta-blockers and digitalis) and we didn`t find any reversible causes for the heart rate acceleration, we opted for rate control with atrioventricular node ablation. To counteract the risk of pacing-induced cardiomyopathy in this patient who would become totally pacemaker-dependent, we successfully performed left bundle branch area pacing. Because the patient`s ICD had a DF-1 connection and the battery had a long life remaining, we connected the physiological pacing lead to the IS-1 sense-pace port of the ICD. The 6-month follow-up showed an improvement in left ventricular function with no more inappropriate shocks.

Conclusions

Left bundle branch area pacing and atrioventricular node ablation in patients with an implantable single-chamber DF-1 defibrillator and fast-conducting permanent atrial fibrillation is a cost-efficient and very effective method to prevent and treat inappropriate shocks, avoiding the use of an additional dual-chamber or CRT-D device.
Unraveling the interplay between dyskinesia and overactive bladder symptoms in Parkinson’s disease: a comprehensive cohort study based on the long-term follow-up database of Parkinson’s disease
Authors: Jin Hong , Du Yiheng , Yan Jiahui , Zhang Jinru , Cheng Xiaoyu , Mao Chengjie , Chen Jing , Liu Chun-feng
Published: March 2024

Objectives

Overactive bladder (OAB) and dyskinesia are frequent complications in patients with Parkinson’s disease (PD). However, the correlation between OAB and dyskinesia has been insufficiently explored. The purpose of this study was to examine the relationship between dyskinesia, OAB, and clinical characteristics among individuals with PD.

Methods

1338 PD patients were included in the present study. Demographic features were compared between patients with or without dyskinesia and OAB symptoms. Logistic regression was conducted on dyskinesia to screen clinically relevant factors. Overactive Bladder Symptom Score (OABSS) was further used to stratify the association between the severity of OAB and the occurrence of dyskinesia.

Results

This study indicates that both dyskinesia and OAB are significantly related to disease severity and cognitive status. PD patients with dyskinesia and OAB having higher UPDRS scores (p < 0.001), H-Y scores (p < 0.001), NMSQ (p < 0.001) and MoCA scores (p < 0.001), and lower MMSE scores (p < 0.001) are identified. The multivariate logistic regression confirms that disease duration (p = 0.041), LEDD (p < 0.001), UPDRSII (p < 0.001), MoCA (p = 0.024), urgency (p < 0.001), frequency (p < 0.001), and nocturia (p = 0.002) are independent risk factors for dyskinesia. Trend analysis indicates that the risk of dyskinesia significantly increases when patients exhibit moderate to severe OAB symptoms (OABSS > 5) (p < 0.001). No significant interactions were found between OABSS and age, gender, disease duration, LEDD, and NMSQ scores in different subgroups, indicating that dyskinesia is more pronounced in patients with OABSS > 5.

Discussion

This study provides compelling evidence supporting the strong correlation between OAB and dyskinesia in PD patients, emphasizing the presence of shared pathogenic mechanisms between these two conditions. Our findings underscore the importance of considering both OAB and dyskinesia in the clinical management of PD, investigating the intricate connections between OAB and dyskinesia could unveil valuable insights into the complex pathophysiology of PD and potentially identify novel therapeutic targets for more effective PD treatment strategies.
A study on the influencing factors of mental health of Chinese garden workers: a cross-sectional study
Authors: Xie Yujin , Jiao Yang , Shi Lei , Liu Di , Liu Ying , Tang Zhen , Gong Weijun , Yu Hong , Ma Yuanshuo
Published: March 2024

Background

Occupational hazards occur in all walks of life. China’s horticulture industry is undergoing rapid development. However, the mental health of garden workers has not received much attention. This study investigates the mental health status and influencing factors of Chinese garden workers and provides a basis for promoting their mental health and ensuring the healthy development of Chinese horticulture.

Methods

A cross-sectional survey of garden workers in Beijing was conducted from 10 July 2021 to 10 October 2021. A total of 3349 valid questionnaires were recovered, with an effective response rate of 95.69%. Descriptive statistical analysis was carried out on the demographic characteristics, job satisfaction, stress, anxiety, and depression of garden workers, and the influencing factors affecting the mental health of Chinese garden workers were found through a t-test, variance analysis, and ordinal multi-class logistic regression analysis.

Results

Survey respondents were mostly male (54.4%) and under the age of 40 (64.1%). The anxiety and depression symptoms of the garden workers were moderate. Among staff members, 40.2% were in a normal state of stress. Gender, three meals on time, monthly income, and job satisfaction were the factors influencing stress, anxiety, and depression symptoms among garden workers.

Conclusion

Compared to medical staff and other groups, the stress, anxiety, and depression symptoms of Chinese garden workers are severe. Gender, monthly income, and job satisfaction are important factors affecting their mental health. Managers should continuously improve the working environment of garden workers, provide salaries that match their positions, and improve their job recognition and satisfaction to reduce the impact of negative emotions on personal health.