bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing the link between epigenetics and metabolism in acute myeloid leukemia
Authors: Greenwood Dalton L , Ramsey Haley Elizabeth , Madden Matthew Z. , Savona Michael Robert , Rathmell Jeffrey C 
Published: January 2023

Abstract
Hematopoietic stem cells (HSCs) undergo self-renewal or differentiation to generate the many myeloid and lymphoid cells. When dysregulated, cancers such as Acute myeloid leukemia (AML) may develop. AML is characterized by expansion and proliferation of undifferentiated myeloid cells that derive from a Leukemic Stem Cell (LSC) population. AML is the most common form of leukemia with 19,520 new cases in 2018, with an adult five-year survival rate of 24%. Here, we examine a newfound relationship between glutamine metabolism, epigenetics, and targeted differentiation of LSCs in AML to promote disease clearance. Glutamine is catalyzed by glutaminase (GLS) to supply α-ketoglutarate (αKG) to the tricarboxylic acid (TCA) cycle and as substrate to demethylase enzymes. We hypothesize that glutamine metabolism plays an integral role in balancing the fate decision of LSCs and that targeting GLS will impact epigenetic modifications and gene expression to affect cell fate. Glutaminase knockout may also be exploited to promote differentiation of AML LSCs. Preliminary data demonstrates the link between epigenetics and metabolism in AML. We profiled three different AML cell lines’ metabolic responses to INCB54329, an inhibitor of bromodomain proteins. We present a heterogeneous response to INCB54329 in oxygen consumption rate, extracellular acidification rate, reactive oxygen species generation, and mitochondrial mass and membrane potential. The precise function of glutaminolysis in hematopoiesis remains unclear. Unraveling the link between glutamine metabolism, epigenetic modifications, and stem cell function presents a novel therapeutic opportunity for various hematologic malignancies, chief among them acute myeloid leukemia.
Metabolic Reprogramming of Arginine in Tumor Stem Cells Facilitates Immune Escape
Authors: Chen KuanHui , Walker Ameae 
Published: January 2023

Abstract
While numerous studies have focused on metabolic reprogramming that leads to immunosuppression in the primary tumor microenvironment, it is not known whether metabolic reprogramming of metastatic tumor cells contributes to immune escape during travel in an exposed environment where they are subject to immune attack. Tumor stem cells (TSCs) are best known for their contributions to tumor metastasis. Using two models of breast cancer (mouse 4T1 and human BT474), we have determined increased arginine metabolism when TSCs encounter inactive or CD3/CD28 activated effector T cells. This manifests as increased expression of the cationic amino acid transporter 2, SLC7A2. However, other changes in arginine metabolism only occur in TSCs encountering activated T cells, including increased expression/activities of inducible nitric oxide synthase (NOS2), protein arginine deiminase and arginine decarboxylase, and a slightly increased expression/activity of Arginase. Using fluorescent Dansyl-Arginine, we have demonstrated competition between TSCs and T cells for Arginine uptake. Thus, the TSC limits activation and expansion of T cells encountered. Interestingly, a reprogramming of enzymes that favor arginine methylation (increased arginine methyltransferases and decreased arginine demethylase) occurs. As a consequence, there is an increase in secreted asymmetric dimethylarginine (ADMA). Here, we report that giving ADMA to human monocytes leads to polarization of macrophages to the M2 phenotype. In summary, our results show a novel metabolic effect in TSCs by reprogramming arginine uptake, metabolism and modification, which in turn modifies functions in approaching immune cells leading to successful immune escape.
Resident memory (TRM) cells sustain immunity to cancer at sites of frequent metastasis
Authors: Molodtsov Aleksey , Lewis Kathryn , Han Jichang , Vella Jennifer , Zhao Yanding , Malik Brian , Zhang Peisheng , Kolling Fred , Cheng Chao , Huang Yina H , Angeles Christina , Turk Mary Jo 
Published: January 2023

Abstract
Tissue resident memory T cells (TRM cells) have recently been recognized as durable mediators of immunity to cancer. We previously showed that regulatory T cell-depleting immunotherapy of B16 melanoma induces protective TRM cells that persist in the skin of mice that develop autoimmune vitiligo. The goal of the present study was to assess the host-wide diversity and function of memory CD8 T cells throughout peripheral tissues of these mice. Using Pmel transgenic CD8 T cells to track Ag-specific responses revealed the generation of memory T cells with a TRM-like phenotype (CD44hi CD62Llow CD103+CD69+) throughout skin, lungs and liver. Parabiotic transfer/equilibration experiments demonstrated the presence of TRM cells in each peripheral tissue and also, surprisingly, in tumor-draining lymph nodes. Tumor protection experiments in parabiotic mice, and after treatment with the S1PR antagonist FTY720, indicated roles for both TRM cells and circulating memory T cells in providing long-lived protection against melanoma re-challenge at various tissue locations. Single-cell transcriptional profiling of memory CD8 T cells isolated from the skin, lungs, liver, lymph nodes, and spleen indicated the presence of diverse populations with features of both circulating and resident memory, but with TRM cell populations dominating in peripheral tissues and tumor-draining lymph nodes. Moreover, clonally-identical TRM cells in the skin, liver, lungs, and lymph nodes each possessed unique transcriptional features exclusive to their tissue of origin. These studies highlight the tissue-specific adaptations of tumor-reactive TRM cells, and the importance of host-wide TRM responses in providing immunity to cancer.
T cell suppression by the bone microenvironment increases bone metastases from breast cancer in mice
Authors: Arellano Danna L , Verdugo-Meza Andrea , Drescher Florian , Olvera-Rodriguez Felipe , Juarez Patricia , Fournier Pierrick 
Published: January 2023

Abstract
Bone metastases are a frequent complication of breast cancer and cannot be cured. Immunotherapy could be used for their treatment. However, its efficiency could be limited by the ability of T cells to increase bone resorption that supports cancer cell proliferation and bone metastases.
To characterize the effect of T cells on bone metastases, we used a syngeneic mouse model with 4T1 breast cancer cells. When inoculated in normal mice, 4T1 caused more osteolysis as measured on x-rays, compared to SCID and T cell-depleted mice (253% and 61% more, respectively). Histology confirmed that normal mice have an increased tumor burden and number of osteoclasts at the tumor/bone interface compared to SCID mice.
T cells isolated from bone metastases suppressed osteoclast formation ex vivo, in contrast with in vivo data. However, this effect was due to the ex vivo activation of T cells, consistent with decreased levels of Rankl and increased expression of anti-osteoclastic Ifng and Il4 mRNA in activated T cells. In vivo, Ifng was not detected, and levels of pro-osteoclastic Rankl and Tnfa were higher in T cells from bone metastases, suggesting they are pro-osteoclastic, unlike activated T cells.
Culturing bone metastasis T cells ex vivo with ConA or anti-CD3/CD28, failed to increase the expression of the activation marker CD69, confirming the presence of suppressive factors in this microenvironment. Accordingly, there was an increase of MDSCs, including monocytic MDSCs that are PD-L1+ (87%) in 4T1 bone metastases. They could suppress the activation of T cells that are PD-1+ (71%) in bone metastases.
These results suggest that unactivated T cells increase bone metastases and their activation by immunotherapy could be used for the treatment of bone metastases.
Function of T follicular helper cells in anti-tumor immunity
Authors: Nurieva Roza I , Liu Zhongshan , Gangadharan Achintyan , Bieerkehazhi Shayahati , Zhao Yang-Zhi , Alekseev Andrei , Sahoo Anupama 
Published: January 2023

Abstract
Clinical relapse and metastases are the major causes of death in melanoma. Currently, adoptive T cell therapy using tumor-infiltrating lymphocytes rich in cytotoxic CD8+ T cells (CTLs) is one of the promising approaches that helps overcome this major challenge in melanoma; however CTL cell transfer alone does not improve clinical response suggesting a role of helper CD4+ T cells. Recently, it has been noted that infiltration of a CD4+ T helper subset, named as T follicular helper (Tfh) cells into tumor sites correlates with increased survival of cancer patients; however their role in tumor immunity has not been clearly elucidated till date. In our hands, both pre-clinical murine tumor studies and patient studies show correlation between increased number of intratumoral Tfh cells and reduced melanoma tumor growth and improved survival, suggesting the novel function of Tfh cells in promoting anti-tumor immunity against melanoma. Remarkably, transfer of tumor antigen-specific Tfh cells in melanoma tumor-bearing mice results in increased intratumoral CTL number and function, as well as in more efficient tumor eradication, indicating the role of Tfh cells in antitumor immunity by promoting CTL expansion and/or activity. Moreover, we determined that Tfh derived cytokine interleukin (IL)-21 contributes to intratumoral CTL activity. Our results thus for first time indicate the therapeutic potential of Tfh cells in promoting anti-tumor immunity against melanoma and provide the basis for potential usage of these cells to improve current immunotherapy approaches.
Sphingosine-1-phosphate receptor 1 (S1P1) loss mediates T cell sequestration in bone marrow in the setting of intracranial tumors: a novel mode of cancer-induced immunosuppression
Authors: Wilkinson Daniel S , Chongsathidkiet Pakawat , Dechant Cosette , Fecci Peter 
Published: January 2023

Abstract
Glioblastoma (GBM), the most lethal primary brain tumor, proves one of the most immunosuppressive solid tumors. Consequently, immune-based interventions, including immune checkpoint blockade, have largely failed to benefit patients with GBM. Recently, we characterized severe lymphopenia and lymphoid organ contraction in treatment-naïve patients and mice with GBM. Remarkably, bone marrow (BM) proves the lone lymphoid organ not subject to T cell disappearance, instead harboring high numbers of the previously missing T cells. Other tumors, including lung, melanoma, and breast cancers, also accumulate T cells in marrow, but only when these tumors are introduced intracranially. In this study, we sought to determine the mechanism mediating T cell sequestration in the context of intracranial tumors. We found that T cells in the BM of tumor-bearing mice had significantly lower levels of surface sphingosine-1-phosphate receptor 1 (S1P1) compared to controls. Mice that were genetically modified to stabilize S1P1 on the surface of their T cells were resistant to T cell sequestration. Moreover, liberated T cells from these mice were able to synergize with a T cell activating 4-1BB agonist to significantly prolong median survival in GBM mice. Here we describe a novel mode of cancer-induced T cell dysfunction contributed specifically by the intracranial microenvironment: S1P1-mediated BM T-cell sequestration. These findings suggest that the immunoprivileged brain harbors unique mechanisms, usurped by intracranial tumors, for preventing T cell entry into the CNS to favor immune escape. Reversal of such sequestration is anticipated as a promising immunotherapeutic adjunct for both primary brain tumors and brain metastases.
Targeting CD40 enhances antibody- and CD8-mediated protection against respiratory syncytial virus infection
Authors: Muralidharan Abenaya , Russell Marsha , Larocque Louise , Gravel Caroline , Li Changgui , Chen Wangxue , Cyr Terry , Lavoie Jessie R , Farnsworth Aaron , Rosu-Myles Michael , Wang Lisheng , Li Xuguang 
Published: January 2023

Abstract
Respiratory Syncytial Virus (RSV) infects almost all children under the age of one and is the leading cause of hospitalization among infants. It also causes high rates of infection in the elderly and immunocompromised patient populations. Despite several decades of research with dozens of candidate vaccines being vigorously evaluated in pre-clinical and clinical studies, there is no licensed vaccine available to date. A clinical trial conducted in the early 1960s testing a formaldehyde-inactivated RSV (FIRSV) vaccine resulted in enhanced respiratory disease, following subsequent RSV infection, leading to hospitalization of 80% of the participants and 2 deaths. Since then, other forms of RSV vaccine have also been found to induce enhanced disease in preclinical animal studies. Here, we aimed to develop a vaccine that can effectively protect mice from RSV infection and help identify facets of FIRSV-induced enhanced disease. In this study, BALB/c mice were immunized with an adenoviral vector containing the RSV fusion protein (F) fused with CD40 ligand where the CD40 ligand serves two vital functions as a molecular adjuvant and an antigen-targeting molecule. In contrast to the FIRSV vaccine, the vectored vaccine effectively protected animals against RSV without inducing enhanced respiratory disease. This protection involved a robust induction of neutralizing antibodies and memory CD8 T cells, which were not observed in the FIRSV group. Finally, the vectored vaccine was able to elicit long-lasting protection against RSV, which was mediated by increased levels of effector memory CD8 T cell 3 months post-vaccination.
Non-complexed chitosan acts as an adjuvant in an influenza A virus protein vaccine
Authors: Lampe Anna T , Farris Eric J , Ballweg Matthew D , Pannier Angela K , Brown Deborah M 
Published: January 2023

Abstract
During the 2017–18 season influenza A virus (IAV) induced significant morbidity and mortality with the most recent vaccine estimated to be 36% effective in preventing illness. However, IAV vaccines may be improved through the use of adjuvants that enhance or direct specific immune responses. The biomaterial chitosan (CS), a partially deacetylated derivative of chitin, has been used in nucleic acid vaccine strategies for its ability to complex with DNA to form nanoparticles. However, we and others have found that non-complexed CS induces cell death and proinflammatory cytokine responses suggesting that non-complexed CS could act as an adjuvant to enhance immunity to protein vaccination. When bone marrow derived dendritic cells (BMDC) were treated with CS in vitro, we observed increased inflammatory cytokine gene expression, including IL-6. However, at high doses of CS the cytokine response was accompanied by BMDC death. Experiments using J774-Dual™ Cells, a mouse macrophage-like cell line with a Lucia luciferase reporter and a secreted embryonic alkaline phosphatase reporter under the Interferon regulatory factors (IRF) and NF-κB respectively, suggest that CS acts as an adjuvant by activating IRF and low levels of NF-κB. In vivo, when CS was administered with an i.m. protein vaccine, enhanced IgG antibody responses were observed at 3 and 4 weeks post vaccination. As CS is a polymer, the molecular weight (MW) may play a role in adjuvanticity. We have observed that MW may impact IRF and NF-κB activation in vitro, as well as antibody production in vivo. Experiments are underway to determine the level of protection afforded by the enhanced antibody production and to investigate if T cell responses can be augmented by modifying the vaccine regimen.
The complex of poly-γ-glutamic acid and aluminum salts ameliorates the reduced efficacy of the influenza H1N1 vaccine in aged mice
Authors: Yang Jihyun , Kim Jaemoo , Kwak Chaewon , Poo Haryoung 
Published: January 2023

Abstract
Influenza is a highly contagious respiratory disease caused by the influenza A viruses and results in public health threat like seasonal epidemics and sporadic pandemics. Although vaccination is considered to be one of the most effective strategy for preventing the disease, the low efficacy of the influenza vaccine has been reported in the elderly. Here, we examined that the aging-related reduced efficacy of the influenza vaccine can be ameliorated by the complex of poly-γ-glutamic acid (γ-PGA) and alum (PGA/Alum), a novel adjuvant capable of inducing both humoral and cellular immune responses, using an aged mouse model. PGA/Alum induced activation of dendritic cells from aged mice, accompanied with increase of both expression of co-stimulatory molecules and production of pro-inflammatory cytokines. In addition, PGA/Alum enhanced the protective efficacy of pandemic influenza H1N1 (pH1N1) vaccine in aged mice, with earlier virus clearance after A/California/4/2009 (pH1N1) viral challenge, increased hemagglutination-inhibition titers, activity of cytotoxic T lymphocytes, and generation of multifunctional T lymphocytes. Taken together, these results suggest that PGA/Alum is a potent vaccine adjuvant that could improve the reduced vaccine efficacy of aging, thereby leading to prevention of influenza virus infection in the immune compromised populations.
The impact of pre-existing B-cell memory in the response to Influenza vaccination
Authors: Abreu Rodrigo B. , Kirchenbaum Greg A. , Clutter Emily F. , Sautto Giuseppe Andrea , Blackwell Anne-Gaelle B. , Ross Ted M. 
Published: January 2023

Abstract
Influenza is a highly contagious viral respiratory disease with more than 200 thousand cases reported in the US last season (2017/18). Annual vaccination is recommended by the World Health Organization with the goal to reduce influenza severity and limit transmission. However, currently available split inactivated influenza vaccines can only elicit protection up to ~60% in well-matched-strain years. Furthermore, vaccine effectiveness frequently varies between different influenza subtypes within a single influenza season for unclear reasons.
Immunological imprinting from early-life influenza infection can prominently shape the immune response to subsequent infections. Here, the impact of pre-existing B-cell memory in the response to quadrivalent influenza vaccine was assessed. Blood samples were collected from healthy subjects (18 to 85 years old) prior to vaccination and 21–28 days after vaccination with quadrivalent influenza vaccine. Samples were assessed for changes in serological antibodies to the hemagglutinin protein (HA) by ELISA and by hemagglutination-inhibition (HAI) assays against the four strains in the vaccine. The number of antigen specific memory B-cells (Bmem) were quantified by flow cytometry and the polyclonal Bmemresponse was assessed against the HA of the four vaccine strains. Influenza vaccination greatly induces the HA-specific Bmem-cell pool and, despite no differences in antigenicity between the four vaccine components, most individuals are biased towards one of the influenza A or Influenza B vaccine strains. Overall, this study unveils a new mechanism behind the differences in vaccine effectiveness against different influenza subtypes.
Neuraminidase inhibition governs protection efficacy of broadly neutralizing antiinfluenza hemagglutinin stem antibodies
Authors: Kosik Ivan , Angeletti Davide , Gibbs Jmes S. , Angel Mathew , Takeda Kazuyo , Kosikova Martina , Nair Vinod , Hickman Heather D. , Xie Hang , Brooke Christopher C. , Yewdell Jonathan W. 
Published: January 2023

Abstract
There is enormous interest in improving influenza A virus immunization. The most promising target for “universal” flu vaccination is the conserved stem region of the viral hemagglutinin (HA). The HA stem is the target for the vast majority of broadly neutralizing (BN) monoclonal antibodies (Abs). It is well established that BNHA Abs can prevent fusion of the viral and endosomal membranes. A discrepancy between in vitro vs. in vivo efficacy, however, suggests additional mechanisms of action. Recent studies support the role of the BNHA Abs Fc interaction with innate immune effector cells.
Here we show that BNHA mAbs potently inhibit viral neuraminidase (NA) activity against large substrates. To unravel the biological relevance of this activity, we created a panel of recombinant IAVs with shorter or longer NA stalks. Finding that neuraminidase inhibition (NI) activity is inversely proportional to NA stalk length, we use these viruses to show that the NI activity of BNHA Abs is responsible for their ability to block virus release from cells and enhanced neutralization. Critically, we show that NA stalk length governs in vivo protection mediated by BNHA Abs in mice, providing a completely novel mechanism for BNHA Abs in vivo activity. In addition, we demonstrated that the NI activity of BNHA Abs enhances the ability of virus-Ab complexes to activate Fc receptor-bearing cells, and further, that FDA approved small molecule NA inhibitors have a similar effect on Fc-mediated innate immune cell activation, providing a novel mechanism for their clinical activity.
Altogether, our findings provide surprising and clinically relevant insights into the in vivo mechanisms of protection provided by both anti-stem BN antibodies and NA inhibitors.
Development of broadly neutralizing antibodies against influenza viruses from mice immunized with monoglycosylated hemagglutinin
Authors: Ko Yi-An , Yu Yueh-Hsiang , Tseng Yung-Chieh , Ma Che , Lin Kou-I 
Published: January 2023

Abstract
Influenza viruses are respiratory pathogens, which cause seasonal outbreaks and result in more than 250,000 annual deaths worldwide. Vaccine inoculation is the most effective way to prevent the virus transmission. Our previous study showed that mice injected with monoglycosylated hemagglutinin (HAmg) protein vaccine designed from influenza A viruses produced cross-stain reactive antibodies and were protected better than mice injected with fully glycosylated HA (HAfg) after challenge with various influenza viruses at lethal dose. Therefore, we applied single B cell RT-PCR platform to pursue the cross-protective monoclonal antibodies (mAbs) from 2007 A (H1N1) Brisbane (Bris/07) HAmg immunized mice. A monoclonal antibody, 651, was selected, which was able to react with a broad spectrum of H1N1 viruses although it did not provide neutralizing activities. It is noted that 651 mediates antibody dependent cellular cytotoxicity (ADCC) against cells expressing HA from multiple strains of influenza viruses, including 2009 A (H1N1) swine (Cal/09), Bris/07, and H3. Alleviated weight loss and improved survival rate were observed in 651 pre-treated mice as compared with the PBS treated group after Cal/09 or Bris/07 virus infection. Interestingly, there were no protective effects against Cal/09 infection in 651 treated FcγR knockout mice. Functionally, proinflammatory cytokines accumulation in lung was ameliorated in Cal/09 infected mice pre-treated with 651. The percentage of alveolar macrophages was recovered in 651 pre-treated mice as compared with the PBS pre-treated mice after Cal/09 infection. Together, this study reveals a potent mAb that possesses broad-spectrum protective effects through the effector function of antibody.