bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct requirements for the cytokine-mediated activation of NKT and NK cells during viral infection. (45.16)
Authors: Tyznik Aaron , Verma Shilpi , Kronenberg Mitchell , Benedict Chris 
Published: January 2023

Abstract
Innate immune cells respond rapidly and provide protection early following infections. We have studied the roles of two innate lymphocyte cell types, natural killer (NK) cells and natural killer T cells (NKT cells) in the protective response to mouse cytomegalovirus (MCMV), a β herpes virus infection. The importance of NK cells for host protection following this infection had been known for many years, but here we establish that NKT cells are also important and that the two cell types have different cytokine requirements for optimal induction of IFNγ. NKT cells are most sensitive to IL-12, when a small amount of IL-18 is present. NK cells, by contrast, are more responsive to IFNβ combined with either IL-18 or IL-12. We further demonstrate that the two cell types are not redundant by identifying dendritic cells, that when infected with MCMV, activates NK cells but does not necessarily activate NKT cells. Consistent with these findings, the activation of NKT cells following MCMV infection was more drastically decreased; compared to NK cells, in mice lacking the ability to produce IL-12. BALB/c mice deficient for NKT cells had increased viral titers, and depletion of NK cells led to a further increase. Our data indicate that NKT and NK cells are both required for maximal MCMV protection, and that they have different requirements for cytokine mediated activation and may reflect the activity of different types of infected antigen presenting cells.
The role of autophagy and amphisomes in virus recognition, TLR 9 recruitment and virus-stimulated IFN-α production by human plasmacytoid dendritic cells (pDC) (45.19)
Authors: Deng Jing , Singh Sukhwinder , Dai Jihong , Fitzgerald-Bocarsly Patricia 
Published: January 2023

Abstract
Human pDC produce large amounts of IFN-α in response to viral nucleic acid stimulation via Toll-like receptor 7/9. However, the mechanisms of virus trafficking and virus-stimulated IFN-α production without infection in pDC remain unclear. In recent studies, we observed double-membrane autophagosomes formed within 2hr stimulation of pDC with HSV, Flu, HIV-1 or CpGA. We also found early endosomal marker Rab5 colocalized with autophagosomal marker LC3 in pDC after stimulation with HSV-GFP virus, indicating amphisomes were induced. These amphisomes were accumulated with chloroquine treatment and included internalized HSV-GFP particles. In this study, we knocked down autophagy gene Beclin 1 by siRNA and found virus-induced IFN-α production was significantly suppressed. We further investigated the interactions between early endosomes, autophagosomes and TLR9 after HSV stimulation using imaging flow cytometry: HSV-GFP particles were internalized into early endosomes by endocytosis and are subsequently transported to amphisomes; Concurrent with the trafficking of HSV-GFP, TLR9 rapidly redistributed to HSV-accumulating amphisomes by colocalizing with LC3 within 30min for ligand binding and signal transduction. Collectively, our studies continue to unveil a previously unknown mechanism of autophagy and amphisome formation in virus-induced IFN-α production possibly involving the recognition of virus and the recruitment of TLR9 to sites of virus uptake in human pDC.
The innate function of T cells in control of inflammation (45.21)
Authors: Tang Hong , Du Jie , Feng Jin , Ma Feifei 
Published: January 2023

Abstract
We have previously shown that T cells are both necessary and sufficient to temper Toll like receptor (TLR) mediated inflammatory response to pathogens, in a TCR-independent manner. In addition, CD8 gene targeting (CD8 KO) or CD8+ T cells depletion by antibody significantly reduce cardiac interstitial fibrosis induced by angiotensin II (Ang II) infusion, whereas CD8 KO mice reconstituted with CD8+ T cells become sensitive to Ang II. Most importantly, CD8+ T cells are required for macrophage infiltration and expression of monocyte chemoattractant protein 1 (MCP-1) that are responsible to Ang II-induced cardiac fibrosis. Furthermore, in vitro transwell experiments show that MCP-1 production by macrophages and its chemotaxis effect on macrophage motility require direct contact with activated CD8+ T cells, but independent of T cell receptor (TCR). A similar cardiac fibrotic response to Ang II is observed in both OT-I transgenic mice that expresses a surrogate TCR specific to ovalbumin and in wild type mice. Thus, CD8+ T cells are both necessary and sufficient for macrophage-induced hypertensive cardiac fibrosis. Therefore, TCR-independent activation of macrophages by CD8+ T cells casts yet a novel innate function of T cells that, in addition to suppressing the innate inflammatory response to infections, CD8+ T cells are required to activate inflammatory response of macrophages to danger signals.
Novel early detection test for breast cancer and its recurrence in blood through changes in immuno-biochemical signals (46.12)
Authors: Chandok Meena , Sakthivel Palanikumaran , Chaney Charles , Mccormack Michael , Wagner Kathryn , Mire Gary , Newby John , Parwani Anil , Renee Kathleen 
Published: January 2023

Abstract
We are developing an immune sensor for early detection of breast cancer and its recurrence in blood, based on identifying the earliest specific changes/alterations in the immuno-biochemical signals in different immune components that are distinctly different from those in a healthy immune system. The screening of different immuno-biochemical signals in their native and altered forms in different immune components/cells led to identification of a novel T cell population. Analysis of this T cell population and its immuno-biochemical signals on blood samples from the 4 groups - (i) healthy, (ii) recently diagnosed with invasive breast cancer stage 1{before the onset of treatment/surgery}, (iii) breast cancer treated individuals who had incidence of recurrence/relapse {BCR}, and (iv) breast cancer treated individuals who were disease free {BDF}- was done using multi-parameter flow cytometry. Sixteen molecules, assessed as the most likely candidates for sensing disruptions in the immune pathway, were used in developing a matrix. Care was taken to separate subjects that could confound the immuno-biochemical signals, potentially arising from other immune disorders. The method designed is different from conventional approaches and has the potential to be used as a cost-effective assessment to predict health status.
Defining the role of ICOS and CD28 costimulation in TH17 cell activation, differentiation and tumor immunity (46.29)
Authors: Nelson Michelle , Huff Logan , Rogers Carolyn , Kundimi Sreenath , Paulos Chrystal 
Published: January 2023

Abstract
TH17 cells play an essential role in regulating host defense and exacerbating various autoimmune diseases, but their role in tumor immunity remains incompletely elucidated. We found that CD28 abrogates TH17 expansion and function, while the inducible costimulator (ICOS) augments the generation of polyfunctional TH17 cells. Of clinical importance, ICOS-expanded TH17 cells were superior at killing human tumors compared to cells expanded with CD28. Our objective is to identify how ICOS regulates the differentiation and optimal expansion of TH17 cells that mediate tumor regression. We have polarized human CD4+ T cells towards TH17 with beads expressing anti-CD3 and CD28 and/or ICOS agonists. ICOS costimulation promotes the long-term generation of TH17 cells, determined by CD161 and CCR6 expression and IL-17A production. By sorting peripheral blood cells based on these two receptors, we identified a subset of cells that nearly all produce IL-17 when stimulated with an ICOS agonist. This innovative approach allows us to study the basic biology of IL-17-producing cells and affords us the ease of exclusively enriching them for adoptive immunotherapy for cancer. We are now uncovering new transcription factors uniquely regulated by ICOS that distinctly impact TH17 cells’ phenotype and functional fate. Understanding how ICOS signaling and optimal culture conditions promote TH17 cell function will be instrumental in advancing T cell-based therapies for cancer and infectious diseases.
Systemic 4-1BB activation induces a novel T-cell phenotype driven by high expression of Eomesodermin (46.30)
Authors: Curran Michael , Geiger Theresa , Montalvo Welby , Kim Myoungjoo , Reiner Steven , Al-Shamkhani Aymen , Sun Joseph , Allison James 
Published: January 2023

Abstract
Following treatment with 4-1BB agonist antibody, a novel population of KLRG1+ T-cells infiltrate murine melanoma. Compared to their KLRG1- counterparts, these T-cells express high levels of cytotoxicity associated genes in both the CD4 and CD8 lineages, and exhibit enhanced tumor-specific killing in vitro. The phenotype of these KLRG1+ cells is dependent on high expression of the T-box transcription factor Eomesodermin (Eomes). Interestingly, only activation of 4-1BB, not other TNFR family members generates this phenotype. The root of this difference appears to be that 4-1BB is expressed by antigen presenting cells (APC) which respond to its activation by producing cytokines which promote the development of these Eomes+KLRG1+ T-cells. By analyzing changes in APC cytokine production in vivo, and by using a series of gene knockout mice we have identified the factors necessary to generate this novel T-cell lineage. These T-cells represent a novel polarity we have termed ThEO (CD4) and TcEO (CD8) which resolve multiple questions associated with 4-1BB activation including how 4-1BB enhances tumor-specific cytotoxicity and how 4-1BB can promote tumor immunity while repressing autoimmunity. Understanding the nature of this novel lineage of highly tumoricidal T-cells in both tumor and pathogen-specific immunity may provide critical information for converting sub-optimal anti-tumor responses to therapeutically successful ones.
Enhancing cancer immunotherapy by combining Notch 1 and death receptor activation (46.38)
Authors: Shanker Anil , Malhotra Anshu , Dikov Mikhail , Biktasova Asel , Sayers Thomas , Carbone David 
Published: January 2023

Abstract
Notch signaling plays diverse roles in lymphocyte differentiation and tumor angiogenesis. Our recent findings implicate the role of Notch 1 pathway in promoting antitumor immune effector functions. We explored the effects of Notch 1 stimulation on T cell immunity and its potential pharmacological activation using Delta-like Notch 1 ligand DLL1 cluster in combination with the proteasome inhibitor bortezomib, which could stabilize Notch 1 activation. Bortezomib was found to selectively sensitize solid tumor cells to apoptosis by upregulating death receptors on tumor cells and amplifying caspase-8 activation in the death-inducing signaling complex. This resulted in reduced pulmonary nodules of injected tumor cells in mice. Additionally, in an in vivo tumor setting, no adverse effects of bortezomib were observed on the antigen-specific T cell proliferative or cytolytic functions. But no long-term survival benefits could be obtained, possibly due to the immunosuppressive effects of the tumor. In our more recent studies, we observed that DLL1-specific immune Notch activation could enhance antitumor T cell immunity by overcoming tumor-associated immunosuppression in D459 and Lewis lung carcinoma models. The results offer a novel combinatorial approach to abrogate the immunosuppressive circuitries operating in the tumor microenvironment with a potential to reduce tumor burden and strengthen tumor-specific immune responses.
Inducible B effector cells (iBECs) for cancer immunotherapy (46.4)
Authors: Ng Spencer , Penafuerte Claudia , Galipeau Jacques 
Published: January 2023

Abstract
While cellular immunotherapy for malignances has traditionally focused on the development and manipulation of tumor targeted DCs, T and NK cells, B cells have remained vastly underutilized as a potential source for adoptive cell therapy. Here we demonstrate that B cells stimulated with FIST-2, a novel chimeric protein consisting of IL-2 fused to the ectodomain of the TGFβ receptor (type II), can adopt an effector phenotype with potent antitumor activity. Treatment with FIST-2 induces naïve splenic B cells to become B effector cells (iBECs), characterized by hyperphosphorylation of STAT3 and 5 downstream of the IL-2 receptor, upregulation of transcription factor, T-bet, and secretion of pro-inflammatory cytokines: IFNγ, TNFα and IL-6. iBECs retained their B cell identity by CD19 and PAX5 expression, but adopted an enhanced APC phenotype through upregulation of cell surface markers associated with antigen presentation and co-stimulation, including: MHC-II, CD80 and CD86. To determine whether iBECs conferred antitumor immunity, we utilized a mouse model of lymphoma expressing ovalbumin (EG.7-OVA). Syngeneic iBECs pulsed with OVA were able to activate OVA-specific OT-I and OT-II T cells in vitro, suggesting that they act as APCs. In vivo administration of OVA-pulsed iBECs protected immunocompetent C57BL/6 mice from EG.7-OVA tumor challenge, and promoted tumor regression in mice with pre-established tumors. These data support the concept of B cell-based adoptive immunotherapy.
Anti-cancer mechanism of the flavonoid icariin (ICA) and its derivative ICT on the tumor microenvironment (46.41)
Authors: Eksioglu Erika , Zhou Jun-Min , Chen Xianghong , Fortenbery Nicole , Latimer Helen , Rasche Sarah , Djeu Julie , Wei Sheng 
Published: January 2023

Abstract
Flavonoids are a group of polyphenolic compounds, commonly found on plants with many biological abilities. Those obtained from the natural derivatives of Herba Epimedii, specifically its active compound icariin (ICA) and a recently described derivative named 3, 5, 7-Trihydroxy-4'-methoxy-8-(3-hydroxy-3-methylbutyl)-flavone (ICT), have been shown to have strong immunomodulatory and anti-tumorigenic effects, including profound effects on myeloid-derived suppressive cells (MDSC), MRP8/14, TLR4 and STAT3 which correlated with a robust decrease in tumor burden in mice. These cells are a suppressive component of the tumor microenvironment that has been determined to play a pivotal role in the maintenance and progression of cancer. They contribute to the up-regulation of inflammatory mediators correlated with tumor progression as well as many other immune suppressive factors. While strides have been made in recognizing the role of these compounds on their therapeutic potential against cancer, their mechanisms of action are poorly understood. In particular we hypothesized that the effect on MDSC is linked to the inhibition of PDE5. We also hypothesized that the effect of these compounds on inflammatory pathways is mediated by the activation and perhaps upregulation of phosphatases which help modulate MDSC activation.
Effective age-specific tumor immunotherapy for B16 melanoma by targeting age-related immune dysfunction (46.42)
Authors: Hurez Vincent , Daniel Benjamin , Liu Aijie , Sun Lishi , Shin Tahiro , Zhang Bin , Curiel Tyler 
Published: January 2023

Abstract
Age is the biggest risk factor for cancer but most studies are in young hosts. We mitigated age-specific tumor-related immune dysfunction to develop immunotherapy for B16 melanoma effective in aged hosts. Young and aged CD4+CD25hi regulatory T cells (Tregs) had similar in vitro function and in vivo tumor-associated increases, but denileukin diftitox (DT)-mediated Treg depletion improved tumor-specific immunity and was clinically effective only in young mice. Aged mice had more basal and tumor-related myeloid derived suppressor cells (MDSC). Depleting MDSC with anti-Gr-1 Ab improved tumor-specific immunity and clinical response better in aged versus young mice. Treg depletion significantly increased MDSC in aged but not young mice, suggesting age-related Treg control of MDSC. In vitro, Treg from aged tumor bearing mice suppressed GM-CSF-induced bone marrow MDSC differentiation. Treg depletion + anti-Gr-1 Ab was more efficacious than anti-Gr-1 alone in aged B16-bearing mice but was no better than Treg depletion alone in young mice. In MC-38 colon cancer, DT and anti-Gr-1 Ab effects were similar in young and aged hosts. Thus aged anti-tumor immune effector cells are competent to combat tumor when tumor-associated immune dysfunction is appropriately mitigated, and age-related immune dysfunction is tumor-dependent. Tailoring immunotherapy to counter age-related, tumor-associated immune dysfunctions remarkably improves cancer immunotherapy for aged patients with specific tumors.
Foxp1 Regulates Anti-tumor Effector Functions of CD8+ T cells in Ovarian Cancer (46.46)
Authors: Stephen Tom , Takata Hiroshi , Feng Xiaoming , Wang Haikun , Rutkowski Melanie , Allegrezza Michael , Hu Hui , Conejo-Garcia Jose 
Published: January 2023

Abstract
T cell based adoptive immunotherapy induces potent anti-tumor response in many cancers. Highly immunosuppressive tumor microenvironment, however, severely impairs effector functions and survival of transferred T cells. In order to gain the best possible immune elimination of tumor cells, specific molecular changes that impair T cell effector functions in the tumor microenvironment need to be identified and targeted. We recently reported that transcription factor Foxp1 critically regulates T cell effector functions as Foxp1-deficient CD8+T cells are better effectors. Here we demonstrate that immunosuppressive tumor microenvironment results in the upregulation of Foxp1 in tumor-reactive T cells, and impairs their effector functions. Consequently, mice bearing ovarian tumors survived significantly longer upon receiving adoptively transferred tumor-primed Foxp1-deficient T cells. In vitro studies further showed that Foxp1-deficient CD8+ T cells can proliferate better in the presence of immunosuppressive TGFb1. Analysis of adoptively transferred T cells showed that, compared to WT CD8+ T cells, Foxp1-deficient CD8+, but not CD4+, T cells survive better in the immunosuppressive tumor microenvironment. Tumor bearing mice receiving Foxp1-deficient effector T cells rejected secondary tumors indicating generation of anti-tumor T cell memory. Our findings indicate that targeting the transcription factor Foxp1 on effector T cells can dramatically improve anti-tumor immunotherapy.
Use of alloreactivity to generate in vivo anti-leukemic responses (46.48)
Authors: Fast Loren , Reagan John , Quesenberry Peter 
Published: January 2023

Abstract
A previous clinical trial demonstrated that infusion of haploidentical G-CSF mobilized WBC (1 - 2 x 10^8 cells/kg) into patients with refractory hematological malignancies (100 cGy irradiation) resulted in a high frequency of anti-leukemic responses including some complete responses despite a lack of detectable donor cell persistence beyond two weeks. Beyond a cytokine storm, no effector mechanisms were defined. It is possible that alloreactive responses were either capable of directly attacking the leukemic cells or reactivating the patient’s anti-leukemic effector cells that were already present via cross-reactivity. PBMNC were obtained from the blood of newly diagnosed leukemic patients, and separated into CD3- and CD3+ populations. The patient’s CD3+ cells were used as responder cells in a mixed lymphocyte culture and stimulated with mitomycin C treated patient’s CD3- cells or PBMNC from allogeneic normal donors chosen at random. On day 7, the effector cells were collected and tested for their ability to lyse 51Cr labeled patient CD3- cells. The results showed that the patient’s CD3+ cells stimulated with allogeneic PBMNC were able to generate anti-leukemic responses in a stimulator dependent fashion. Thus, this assay may be useful for predicting which donor would be best for patients receiving cellular immunotherapy and may also be useful for the defining the anti-leukemic effector cells that are present with this form of cellular immunotherapy.
Characterization and Manipulation of NZB miR15a/16-1 loci for CLL Therapy (46.50)
Authors: Kasar Siddha , Underbayev Chingiz , Yuan Yao , Raveche Elizabeth 
Published: January 2023

Abstract
Chronic Lymphocytic Leukemia (CLL) is a malignancy characterized by accumulation of mature CD5+ B-cells in peripheral lymphoid organs, bone marrow and blood and is incurable with conventional therapy. We have previously shown that similar to human B-CLL cells, NZB mice (de novo mouse model of CLL) have 50% less level of miR15a/16-1 that is associated with a mutation and deletion in the miR15a/16-1 region. The NZB loci lead to a processing defect inhibiting the conversion of pri-miR15a/16-1 to pre-miR15a/16-1. We hypothesized that exogenously increasing its expression would lead to increased apoptosis in tumor cells. Using a lentiviral delivery system, we were able to stably increase the level of these two microRNAs in LNC (NZB derived B-CLL cell line). The apoptosis observed in miR-GFP transduced LNC was twice as much as in LNC transduced with GFP lentivirus (control). In addition to the miR defect, B-CLL cells have a very high level of B-cell specific activator protein (BSAP) and this prevents their terminal differentiation. Recent reports have suggested that BSAP and miR15a/16-1 form an autoregulatory loop. Alternatively, we found that the miR defect can also be corrected by knocking down BSAP (using RNAi) leading to a cell cycle arrest. The second strategy is clinically relevant, since developing a BSAP inhibitor is more feasible than systemic miR delivery. Based on our findings we propose that targeting BSAP could be used as a novel therapeutic strategy for B-CLL.
SLAMF1/CD150 is a signaling receptor in a subset of chronic lymphocytic leukemia cells (46.9)
Authors: Bologna Cinzia , Buonincontri Roberta , Serra Sara , Vaisitti Tiziana , Audrito Valentina , Brusa Davide , Rossi Davide , Coscia Marta , Gaidano Gianluca , Terhorst Cox , Deaglio Silvia 
Published: January 2023

Abstract
Human SLAMF1 (CD150) is expressed on T, B, NK, and dendritic cells where it acts as a co-activator through self interactions. Gene expression profiling has identified SLAMF1 as part of the genetic signature characterizing chronic lymphocytic leukemia (CLL) patients with favorable prognosis. The analysis of SLAMF1 expression on the CD19+ fraction of 220 patients with CLL revealed highly variable levels. Statistical analyses indicate that patients characterized by a good prognosis express higher levels of SLAMF1 compared to the counterpart. Furthermore, patients with less than 6% SLAMF1+/CD19+ CLL cells had a significantly longer treatment free survival (median 6.4 in SLAMF1- vs 1.2 years in SLAMF1+ patients, P=.002). SLAMF1 expression was also inversely correlated with CD38, CD49d and ZAP-70, and positively associated with the presence of somatic mutations in the IgHV genes, all molecular hallmarks of good prognosis. Incubation of CLL cells with anti-SLAMF1 mAb induced a robust tyrosine phosphorylation pattern, mediated by the EAT-2 adaptor. Activated intracellular molecules included lyn, vav-1, p38 and jnk. Co-crosslinking of SLAMF1 with sIgM prolonged phosphorylation of p38 and jnk and increased the percentage of CLL cells undergoing apoptosis, as compared to either signal alone. In conclusion, SLAMF1 represents a novel marker for CLL patients with a favorable prognosis. Functional data suggest that it may function together with the BCR in regulating CLL apoptosis.