bluuebunny/crossref_metadata_2025_split huggingface dataset:
The intrinsic pro-tumorigenic role of IRF1
Authors: Shao Lulu , Hou Weizhou , Scharping Nicole , Delgoffe Greg M. , Sarkar Saumendra N. 
Published: January 2023

Abstract
Interferon regulatory factor 1 (IRF1) is a nuclear transcription factor which appears to have anti-tumor activity in human and mice. IRF1 can be induced by interferon-gamma (IFNγ). Although recent studies indicated that the IFNγ-PD-L1 axis played an important role during T cell exhaustion, and promoted tumorigenesis, the cell intrinsic role of IRF1 is not completely clear in this context. In this study, we investigated the intrinsic role of IRF1 during tumor progression. We generated several IRF1-deficient (IRF1-KO) murine tumor cell lines (CT26, MC38 and B16-F10) via CRISPR/Cas9-mediated genome editing, and compared their growth rates with wild type (WT) cells both in vitro and in vivo using syngeneic mouse tumor models. We found that the loss of IRF1 did not affect cell growth rates in vitro. However, the IRF1-KO cells showed significantly slower tumor growth than WT cells in mice models. Depletion of CD8+ T cell using antibody rescued the ability of IRF1-KO cells to grow tumors. Furthermore, analysis of tumor infiltrating T cells showed more activated CD8+ T cells and less exhausted T cells in IRF1-KO induced tumors than those induced by WT cells. To confirm whether these results were caused by IFNγ-IRF1-PD-L1 axis, we evaluated IFNγ-induced inhibitory ligands on tumor cells in both WT and IRF1 KO cell lines. We found that the expression levels of MHC class I were not affected by loss of IRF1, whereas, the induction of PD-L1 by IFNγ was abolished in IRF1 KO cells. In conclusion, intrinsic loss of IRF1 in tumor cells significantly reduces tumorigenesis in solid tumors. This phenomenon depends on the regulation of PD-L1 expression on tumor cells via IFNγ-IRF1-PD-L1 axis, and eventually affecting host anti-tumor immune responses, such as CD8+ T cells.
ST8Sia6 overexpression in cancer and its effect on the tumor microenvironment
Authors: Friedman David J. , Shapiro Michael J. , Shapiro Virginia Smith 
Published: January 2023

Abstract
Modulating T-cell activity has been the primary focus in cancer immunotherapy. However, cancer cells can promote differentiation of macrophages into tolerogenic “M2” macrophages, which support tumor growth. Macrophage differentiation by cancer cells is influenced by many receptors including Siglec-E. Siglec-E recognizes α2,8-linked disialic acids on O-linked glycoproteins, and functions to inhibit activation of innate immune cells including macrophages. One enzyme that generates α2,8-linked disialic acids is ST8Sia6. COSMIC database analysis revealed that 389 tumors overexpressed, while none under-expressed, ST8Sia6, indicating a potential selective advantage for increased ST8Sia6 expression on tumors. Additionally, on a variety of cancers many patients with high expression of ST8Sia6 exhibit reduced survival as compared to patients with low expression. Therefore, we hypothesized that ST8Sia6 overexpressing tumors will engage Siglec-E, causing differentiation and expansion of M2 macrophages, and accelerating tumor growth. We demonstrated that ST8Sia6 increases M2 macrophage polarization in cell lines expressing ST8Sia6 compared to parental lines in vitro and in vivo. In vivo murine models also demonstrate increased tumor burden and reduced survival in mice injected with ST8Sia6 overexpressing MC38 tumors. Therefore, ST8Sia6 expression in tumors may suppress the immune response and promote tumor growth. ST8Sia6 may prove to be a “druggable” target for future cancer immunotherapies.
Single cell sequencing reveals regulatory role for T cell expressed microRNA-155 within the tumor microenvironment.
Authors: Huffaker Thomas , O’Connell Ryan 
Published: January 2023

Abstract
MicroRNA-155 (miR-155) is a pro-inflammatory miRNA that has been shown to regulate antitumor immunity. We recently demonstrated, utilizing miR-155 T cell conditional knockout mice (TCKO), that miR-155 is required by T cells to inhibit the growth of transplanted B16f10 melanoma tumors. To further understand the role of miR-155 expression within tumor infiltrating T cells and their impact upon the tumor microenvironment, we performed 10× single cell RNA-sequencing on tumor infiltrating immune cells from miR-155 TCKO mice and controls. At 12 days post administration of B16f10 OVA syngeneic tumors, CD45+ cells from the tumors of miR-155 TCKO mice and control mice were sorted via flow cytometry and single cell sequencing was performed. Results indicate that the immune cell landscape within these tumors consists of at least 11 distinct populations. This included an expanded population of Arg1 and Ym1 expressing cells of the myeloid lineage in tumors from miR-155 TCKO mice. Tumors from these mice were also deficient in a specific subset of CD8+ T cells that highly express interferon gamma, granzyme B, and perforin. miR-155 host gene was expressed by this population of effector CD8+ T cells in Wt control mice. These results demonstrate the utility of using single cell RNA-Seq to comprehensively profile immune cells that are responding to solid tumors. Further, the data clearly indicate that miR-155 expression by T cells is necessary for their recruitment and production of antitumor molecules, while at the same time preventing the accumulation of myeloid populations with known roles in suppressing tumor immunity. These data have implications for manipulating miR-155 in the clinic as a means to bolster tumor immunotherapy.
DcR3 acts as a tumor marker of metastatic cancers
Authors: Wan Xiaochun , Li Junxin 
Published: January 2023

Abstract
Decoy receptor 3 (DcR3) is a soluble protein that competitively binds Fas ligand and has an anti-apoptotic role. Abnormally elevated DcR3 in malignant tumors may help cancer cells metastasize by suppressing immune responses and establishing metastatic lesions. However, whether DcR3 is valuable in differentiating cancer metastasis from non-metastasis remains largely unclear. In this study, we produced anti-DcR3 monoclonal antibodies and established a sensitive ELISA (11–12000 pg/ml, R2= 0.9941) to measure serum levels of DcR3 in cancer patients. DcR3 was significantly elevated in gastric cancer (2.04 ± 1.01, P = 0.0061), lymphoma (1.62 ± 0.75, P = 0.041) and breast cancer (1.53 ± 0.51, P = 0.023). ROC (Receiver Operating Characteristic) analysis suggested DcR3 was a suitable biomarker for the diagnosis of gastric cancer (Sensitivity = 85.7%, Specificity = 90.0%, AUC = 82.3%). Importantly, serum DcR3 was positively correlated with platelet distribution width (PDW) (P = 2.45×10−6, R = 0.63) in metastatic cancers while negatively correlated with hemoglobin (HGB) (P = 0.002, R = −0.59) and hematocrit (HCT) (P = 0.001, R = −0.62) in non-metastatic cancers. DcR3×PDW÷(HGB×HCT), the novel indicator could be used to differentiate cancer metastasis from non-metastasis (Sensitivity = 75.0%, Specificity = 80.9%, AUC = 79.0%). These results reveal that DcR3 has a predictive value for cancer metastasis in combination with hematological traits.
Tumor necrosis factor receptor II (TNFR2) promotes the growth of mouse CT26 colon cancer
Authors: Chen Xin , Li Ping , Yang Xinyu , Miao Xiaosu , Luo Hua 
Published: January 2023

Abstract
TNFR2 is expressed by several tumor cells including colon cancer, Hodgkin lymphoma, myeloma, renal carcinoma and ovarian cancer. Recently, TNFR2 is becoming appreciated as an oncogene. However, the exact role of TNFR2 on the tumor development remains to be fully understood. In this study, we examined the tumorigenesis and growth of mouse CT26 colon cancer cell lines with genetically modified TNFR2 expression in syngeneic Balb/c mice. We used CRISPR/Cas9- induced loss-of-function approaches to obtain stable TNFR2 KO CT26 cell line and gain-of-function techniques to obtain TNFR2 overexpressing CT26 cell line. WT, TNFR2 KO and TNFR2 overexpressing CT26 cells were inoculated s.c. into the mice. Although TNFR2 overexpressing CT26 tumor grew markedly faster than TNFR2 KO CT26 cells, there was no difference in the initial tumorigenesis, Intriguingly, all TNFR2 KO CT26 tumors completely regressed 2 weeks after inoculation. The proportion of Foxp3+ Tregs, as well as their TNFR2 expression, in the draining LNs was markedly higher in mice bearing TNFR2 overexpressing CT26 tumor. The levels of soluble TNFR2 in the peripheral blood of CT26 tumor bearing mice were ~3 folds higher than that in tumor free mice, which is comparable with the elevated levels of soluble TNFR2 in human tumor patients. In mice bearing TNFR2 overexpressing CT26 tumors, the levels of soluble TNFR2 was &gt;4 folds higher than that in mice bearing WT CT26 tumors. In vitro, exogenous TNF was able to up-regulate TNFR2 surface expression on CT26 tumor cells. Taken together, our data suggest that TNF-TNFR2 signaling pathway may play a major role in tumor growth and tumor immune evasion, and thus may represent an important therapeutic target.
Cheating death: a Fas-41BB immunomodulatory fusion protein obviates a death signal to enhance T cell function and adoptive therapy targeting leukemia and solid tumors
Authors: Oda Shannon K. , Anderson Kristin G. , Garcia Nicolas , Ravikumar Pranali , Daman Andrew , Bonson Patrick , Greenberg Philip D. 
Published: January 2023

Abstract
Fas/FasL signaling plays a significant role in the generation and persistence of tumors. We and others have detected FasL expression in the tumor microenvironment (TME) of human ovarian, pancreatic, and other cancers, where it can function to protect tumor cells from tumor-infiltrating lymphocytes. Adoptive immunotherapy, a promising treatment option, uses genetically modified T cells to eliminate tumors. However, efficacy of T cell immunotherapy is dampened by limited costimulation as well as increased inhibitory and death signals in the TME. We previously showed enhanced therapeutic efficacy by engineering T cells to express an immunomodulatory fusion protein (IFP) to convert the inhibitory CD200R signal to a costimulatory CD28 signal and questioned if IFPs could use a 4-1BB signal to enhance in vivo persistence and memory formation. 4-1BB forms a trimer when binding its ligand, that is requisite for an effective costimulatory signal. We and others engineered T cells to express 4-1BB with an ectodomain that dimerizes, however this IFP did not improve T cell function. We hypothesized a Fas IFP with a 4-1BB signal would effectively replace Fas signaling and provide costimulation, as Fas also trimerizes when engaged by ligand. T cells transduced with the Fas-4-1BB IFP exhibited enhanced accumulation and function in vitro. In a model of leukemia, Fas-4-1BB-transduced T cells eradicated otherwise lethal disease and exhibited increased persistence. Preliminary data in the autochthonous KPC pancreatic and ID8 ovarian cancer models support increased efficacy. We describe for the first time that an IFP can generate an effective 4-1BB signal to overcome obstacles in the TME and enhance T cell immunotherapy of solid and liquid malignancies.
Adoptive cell therapy using allergen-specific CD4-CD8-T regulatory cells to treat airway allergic disease in mice
Authors: Tian Dan , Zhang Chunpan , Jin Hua , Tian Yue , Sun Guangyong , Liu Kai , Shi Wen , Zhang Dong 
Published: January 2023

Abstract
Allergic asthma is a chronic inflammatory disorder of the airways. Traditional therapeutic strategies have been unsatisfactory in controlling the underlying pathology. New approaches that specific overcome the detrimental effects of immune dysregulation in allergic asthma are required. We have identified a new differentiation pathway for CD4−CD8− (double negative, DN) T cells that exhibits the potent immunosuppressive function in vitro and in vivo.
In this study, we adoptive transferred OVA323–339 primed DNT cells to a mouse model of ovalbumin (OVA)-induced allergic asthma intravenously. The adoptive transferred DN T cells mainly migrated to mediastinal lymph node and lung, exerted strong suppression on CD11b+ dendritic cells, T follicular helper (Tfh) cell proliferation and IL-21 secretion, which resulted in significantly ameliorated airway hyperresponsiveness, lung inflammation and granulocyte accumulation, markedly reduced mucus formation and OVA-IgG/IgE production.
To understand the antigen-specific mechanism of DN T cell, which is lack of CD4 molecule, we investigated the role of Lag3 in allergen recognition of DN T cell. We demonstrated that Lag3 deficiency impaired the generation of OVA-specific DN T cells. DN T cells acquired MHC-II of dendritic cells to obtain antigen specificity with the assistance of Lag3 molecule mainly through a trogocytosis process.
The effectiveness of ex vivo generated OVA-specific DN T cell to alleviate airway inflammation support the concept and the feasibility of potentially utilizing this novel cell-based therapeutic approach clinically for the treatment of allergic asthma.
Differential induction of antibodies against immunogenic V1V2 and V3 regions of HIV-1 envelope by immune complex vaccines
Authors: Hioe Catarina E. , Kumar Rajnish , Upadhyay Chitra , Fox Alicia , Itri Vincenza , Peachman Kristina , Rao Mangala , Jiang Xungqing , Kong Xiangpeng , Zolla-Pazner Susan 
Published: January 2023

Abstract
Antibodies (Abs) are critical elements of immune defense against HIV-1. Abs induced during infection or after immunization with HIV-1 envelope (Env)-based vaccines often target immunogenic sites on the V1V2 and V3 regions of HIV-1 Env. Most of these Abs have poor neutralizing activity but display Fc functions, such as Ab-dependent cellular cytotoxicity and phagocytosis, that also can contribute to protection against HIV-1. Nonetheless, eliciting high-titer and durable Ab responses to V1V2 and V3 by active vaccination remains a challenge.
Our previous studies have shown Env/mAb immune complexes (ICs) to be superior vaccine immunogens vs Env alone for eliciting anti-V3 Abs. Our current study examined parameters that enhance IC immunogenicity by comparing IC vaccines made with different HIV Env (gp120-JRFL clade B, gp140-CN54 clade C, gp120-A244 clade E) and mAbs of different specificities (V3, V1V2, CD4 binding site [CD4bs]) in BALB/c mice. The data showed that greater titers of V3-binding and virus neutralizing Abs were induced by ICs made of clade B gp120 and mAbs to V1V2 or CD4bs vs uncomplexed gp120. IC made of clade B gp120 and mAb to V1V2 also induced greater V1V2-specific Ab-dependent phagocytosis. On the other hand, the gp120/V3 mAb IC elicited lower Ab titers to V3, V1V2, and gp120. Immunization with IC made with clade C gp140 and CD4bs mAb also induced higher titer of anti-V3 Abs, although it was not as potent as the clade B IC. In contrast, ICs made with clade E gp120 did not have the same effect. These results demonstrate the capacity of IC vaccines made of HIV-1 Env and selected anti-Env mAbs to modulate induction of Ab responses to V1V2 and V3, and this activity depends on the Env proteins used to form ICs.
Monoclonal antibody prophylaxis protects against lethal Ebola virus infection
Authors: James Rebekah , Stonier Spencer W. , Bakken Russell , Bornholdt Zachary A. , Dye John M. 
Published: January 2023

Abstract
Pan-Ebolavirus neutralizing antibodies MBP087 and MBP047, derived from a human EBOV survivor, are protective in rodent models when administered therapeutically two days after infection. Mutations in the Fc region of hIgG, known as YTE and XTND, prolong the half-life of hIgG so we incorporated these mutations into the framework of MBP087 an MBP047 to determine if the longer half-lives could provide protection with an extended pretreatment prior to infection. Wildtype (wt) (C57Bl/6) and mFcRn−/− hFcRn tg+/+ mice were given a single dose of Nicotiana (N)-derived MBP087 or MBP047 bearing a wt antibody framework or with the YTE or XTND mutations. MBP087-N or MBP087-YTE-N protected 80–100% of hFcRn tg mice against EBOV when administered 30 or 60 days prior to infection. Surprisingly, both MBP087-N and MBP087-XTND-N were also highly protective (80%) in wt mice over the same 30 or 60d window, showing surprising longevity and potency. Interestingly, wt MBP047-N protected 80% of wt mice when administered 30d prior to infection but provided little protection over 60d, regardless of YTE or XTND mutations. These data indicate that the utility of pan-Ebolavirus neutralizing antibodies can be expanded from a therapeutic use to a prophylactic use 30–60d prior to exposure. Expanding the utility of antibodies to prophylaxis may be advantageous in cases where vaccines are lacking or contraindicated due to patient restrictions.
Novel MVA-based vaccine expressing influenza NP and M1 activates cross-reactive T cell responses in human nasopharynx-associated lymphoid tissue (NALT)
Authors: Puksuriwong Suttida , Ahmed Muhammad Shamsher , Sharma Ravi , Krishnan Madhan , Sood Salil , McCormick Max , Leong Sam , Lambe Teresa , McNamara Paul , Gilbert Sarah C. , Zhang Qibo 
Published: January 2023

Abstract
Influenza virus infection continues to cause widespread morbidity and mortality, resulting in major challenges for healthcare systems. Current influenza vaccines are of limited efficacy against mismatched or emerging new virus strains. Recent efforts are focused on the development of novel vaccines capable of conferring broad protection against various influenza virus subtypes. We have studied the potential of Modified Vaccinia Ankara (MVA)-vectored vaccines expressing nucleoprotein and matrix protein 1 (MVA-NP+M1) to induce cross-reactive mucosal immunity using human adenotonsillar mononuclear cell (MNC) culture system with flow cytometry and ELISPOT analysis.
Influenza NP and M1 antigens were abundantly expressed following vaccine stimulation in MNC particularly in B cells and dendritic cells. M1-specific T cell response was analyzed in detail, and MVA-NP+M1 was shown to activate IFN-γ-producing CD8+ T cells against conserved M1 epitopes. M158–66-specific CD8+ T cells in HLA-matched individuals were markedly increased in an age-dependent manner. These M1-specific T cells coexpressed cytotoxic molecules such as perforin and granzyme A and B. Upon the recognition of M158–66 peptide, these cells displayed marked increase in surface CD107a expression (implicating degranulation), together with the production of pro-inflammatory cytokines including IFN-γ and TNF-α, that correlated to their ability to kill the peptide-pulsed target cells.
In summary, we showed MVA-NP+M1 activates conserved influenza antigen-specific cytotoxic T cell response in human NALT. The results suggest MVA-NP+M1 vaccine has the potential to induce cross-reactive mucosal T cell immunity against different types of influenza viruses.
Age-specific TLR7/8 adjuvant formulation overcomes hyporesponsiveness to neonatal acellular pertussis vaccination in a mouse model
Authors: Dowling David J. , Smith Alyson J. , Borriello Francesco , Brightman Spencer , Schüller Simone , Bazin Hélène , Burkhart David J. , Levy Ofer , Evans Jay T. 
Published: January 2023

Abstract
Infection is the most common cause of mortality early in life, in large measure due to suboptimal early life vaccination strategies as compared to older age groups. New adjuvants are absolutely cardinal to further optimize current immunization approaches. However, only a few classes of adjuvants are presently incorporated in vaccines approved for human use. Recent advances in the discovery and delivery of Toll-like receptor (TLR) adjuvants have provided a new toolbox for vaccinologists. Prominent among these candidate adjuvants are synthetic small molecule TLR7/8 agonists. The development of an effective infant Bordetella pertussis vaccine is now urgent because of the resurgence of pertussis in many countries, contemporaneous and likely related to the switch from whole cell to acellular vaccines. In this context, age-specific adjuvant strategies may be key to enhance early life immunogenicity by creating a vaccine formulation that induces both robust and persistent immunity (i.e., overcome waning immunity) to B. pertussis. In the present study, we firstly optimized the a) formulation delivery system, b) stability, and c) immunologic activity of novel small molecule imidazoquinoline TLR7/8 adjuvants towards human infant leukocytes. Next, in both adult and neonatal mouse models, we demonstrate that this TLR7/8 adjuvant can overcome neonatal hyporesponsiveness to acellular pertussis vaccination by driving Th1 favoring responses to a licensed acellular vaccine (DTaP). This potent immunization strategy may be of fundamental importance in vaccine development and could represent a new paradigm for effective pertussis immunization in early life.
Innate immunity limits protective adaptive immune responses against pre-erythrocytic malaria infection.
Authors: Minkah Nana K. , Sack Brandon K. , Sheikh Amina A. , Vaughan Ashley M. , Kappe Stefan H.I 
Published: January 2023

Abstract
Immunization with whole pre-erythrocytic stage malaria parasites that infect hepatocytes but are unable to cause blood stage infection constitutes one of the most promising strategies to protect against malaria infection. In rodent malaria models, whole parasite vaccines that exhibit substantial replication within hepatocytes engender superior, long-lasting strain- and stage-transcending immunity as compared to replication-deficient whole parasite vaccines. Liver stage infection with replication-competent Plasmodium parasites induces an innate immune response that is dependent on type I Interferon (IFN-1) signaling. However, it remains unknown how this IFN-1 response contributes to vaccine-engendered adaptive immunity. Using a replication-competent genetically attenuated parasite vaccine in an immunization regimen that confers partial protection in wildtype (WT) mice, we examined vaccine efficacy in mice lacking IRF3 or IFNAR. Surprisingly, IRF3−/− and IFNAR−/− mice showed superior protection against an infectious sporozoite challenge when compared to WT mice. Better protection correlated with a greater frequency of liver-resident memory CD8 T cells in immunized IFNAR−/− mice. Furthermore, IFNAR−/− mice exhibited lower levels of the T cell co-inhibitory receptors, PD-1 and LAG-3, a greater percentage of IFNγ-producing CD8 T cells, and eliminated liver stages more effectively. Taken together, we show that the Plasmodium engendered IFN-1 response impairs the generation of an optimal memory T cell response. To our knowledge, this study is the first description of a detrimental role for IFN-1 signaling on malaria vaccine efficacy and as such may necessitate a paradigm shift in rational malaria vaccine design.