bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD84 is a survival receptor for chronic lymphocytic leukemia cells (P2044)
Authors: Marom Ayelet , Binsky-Ehrenreich Inbal , Sobotta Mirko , Shvidel Lev , Berrebi Alain , Hazan-Halevy Inbal , Kay Sigi , Aloshin Anna , Sagi Irit , Goldenberg David , Leng Lin , Bucala Richard , Herishanu Yair , Haran Michal , Shachar Idit 
Published: January 2023

Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+ B lymphocytes in peripheral blood, lymphoid organs and bone marrow (BM). The main feature of the disease is accumulation of the malignant cells due to decreased apoptosis. CD84 belongs to the Signaling Lymphocyte Activating Molecule (SLAM) family of immunoreceptors, and has an unknown function in CLL cells. Here, we show that the expression of CD84 is significantly elevated from the early stages of the disease, and is regulated by macrophage migration inhibitory factor (MIF) and its receptor, CD74. Activation of cell surface CD84 initiates a signaling cascade that enhances CLL cell survival. Both downmodulation of CD84 expression and its immune-mediated blockade induce cell death in vitro and in vivo. In addition, analysis of samples derived from an on-going clinical trial, in which human subjects were treated with humanized anti-CD74 (milatuzumab), shows a decrease in CD84 mRNA and protein levels in milatuzumab-treated cells. This downregulation was correlated with reduction of Bcl-2 and Mcl-1 expression. Thus, our data show that overexpression of CD84 in CLL is an important survival mechanism that appears to be an early event in the pathogenesis of the disease. These findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway.
Pharmacodynamic impacts of chemotherapy and immunotherapy upon adipose tissue (P2054)
Authors: Myers Cheryl , Pollock Kevin , Bradley Judy , Gorman Jessica , Gendler Sandra , Cohen Peter 
Published: January 2023

Abstract
Recent guidelines by the American Society of Clinical Oncologists recommend that obese individuals receive chemotherapy based on their actual body weight (ABW) without dose reduction. Contrary to prior reports, our own data demonstrate that ABW-dosed chemotherapy or immunotherapy is as effective and well tolerated by obese mice as by lean mice. Nonetheless, obese mice develop significantly greater weight loss in a dose-dependent manner during the entire period that they receive therapy, with corresponding quantifiable reductions in visceral fat depots. This disparity is not explained by altered food intake, as both lean and obese mice experience less than a week of anorexia which does not recur after Cycle 1 of treatment. Furthermore, malabsorption is absent. These observations are relevant to multiple classes of chemo agents. Altered pharmacokinetics of chemotherapy agents in adipose tissue have been reported, yet the pharmacodynamics of obesity remain speculative. Fasting blood glucose monitoring demonstrates glucose level variances which are temporally linked to treatment, rendering it likely that chemotherapy and immunotherapy provoke adipose tissue lipolysis, or alternatively cytoreduction or immunomodulation of adipocyte progenitor cells. Understanding these effects could contribute to improved treatment regimens in the setting of obesity.
Splenectomy restores IFNγ-dependent tumoricidal activity of CD8+ T cells to promote rejection of intraocular tumors by a mechanism requiring macrophages and FasL (P2056)
Authors: McKenna Kyle , Beatty Kelly , Thorne Stephen 
Published: January 2023

Abstract
It is well established that splenectomy terminates ocular immune privilege to promote rejection of intraocular tumors that would otherwise grow progressively in the anterior chamber (a.c.) of the eye. However, the mechanisms of intraocular tumor rejection in splenectomized mice remain undefined. Utilizing E.G7-OVA tumors transplanted in the a.c. of C57Bl/6 mice we identified the requirement for CD8+ T cells. Interestingly, E.G7-OVA tumor growth in both splenectomized and control mice induced expansion and differentiation of OVA specific CD8+ T cells into granzyme B+ CTL that infiltrated ocular tumors in comparable numbers. As splenectomized perforin deficient mice rejected ocular tumors, these data indicated that direct lytic activity was dispensable. Rejection of ocular tumors also required macrophages and immune cell expression of IFNγR1 suggesting that splenectomy restored IFNγ production by CD8+ T cells or rescued IFNγR1 signaling in macrophages. However, IFNγ was expressed by CTL infiltrating ocular tumors of both splenectomized and control mice, and CTL-expressed IFNγ induced expression of nitric-oxide-synthase-2 in intratumoral macrophages. FasL expression was also required for ocular tumor rejection. Based on these data we propose a model in which CD8+ T cells express IFNγ to induce FasL ligand expression by intratumoral macrophages that promotes apoptosis of Fas+ tumor cells.
CpG ODN-dependent MDSC modulations contribute to the efficacy of Ad5-TRAIL/CpG ODN antitumor therapy (P2076)
Authors: James Britnie , Kucaba Tamara , Norian Lyse , Griffith Thomas 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSC) are immature, activated myeloid cells that can suppress T cell function via multiple mechanisms and dampen antitumor immunity. As with many tumor models, we found a high frequency of MDSC in the primary kidney tumor, spleen, and lung metastases in an orthotopic model of advanced renal cell carcinoma (RCC). MDSC from both primary tumor and spleen suppressed T cell proliferation in vitro. However, following treatment of the primary kidney tumor with a recombinant adenovirus encoding TRAIL (Ad-TRAIL) in combination with CpG ODN, MDSC numbers decreased at all aforementioned locations and a robust systemic CD8 T cell-mediated antitumor immune response was initiated that was ultimately responsible for clearing the primary RCC tumors and lung metastases. Subsequent analysis revealed that CpG ODN alone was able to directly modulate MDSC frequency and phenotype at the primary tumor site and metastatic lung, resulting in a more “mature” phenotype as seen by increases in CD40, CD80, and CD11c and decreases in Gr-1. Interestingly, concomitant depletion of MDSC, which alone lead to tumor regression, did not exhibit any synergistic effects with therapy, suggesting that Ad-TRAIL/CpG alone overcomes MDSC suppression. These data suggest that while CpG ODN may play many roles contributing to the antitumor immune response, one important role appears to be the modulation of the suppressive MDSC population.
Multidisciplinary approaches to enhance BRAF targeted therapy in melanoma (P2092)
Authors: Pangigadde Pradeepa Narayana , Tan Thomas , Ferrone Soldano , Karre Klas , Colucci Francesco , Carbone Ennio 
Published: January 2023

Abstract
40-50% of patients with melanoma are identified with BRAF mutations. About 80% of the BRAF mutations carry the V600E mutation. These patients are treated with BRAF inhibitors alone or in combination with other cell signaling pathway inhibitors. However, a relapse of the disease is observed within 6-8 months after the commencement of the therapy. Some studies hint that NK cell based therapy can be effective in controlling melanoma. In this study multidisciplinary approaches were tested to understand the mechanism of Vemurafenib resistance by a BRAFV600E melanoma. Vemurafenib is a BRAFV600E inhibitor. Vemurafenib resistant melanoma cell lines were raised from the sensitive cell lines by drug treatment till 80-90% of cells showed resistance. Both the resistant and sensitive cell lines were tested in a NK cell cytotoxicity assay in vitro by standard 51Cr-release assay. The Vemurafenib resistant cell lines were found to have a reduced sensitivity to NK cell killing. Though there was no significant difference in expression of NK cell activating ligands on the surface between the resistant and sensitive cell lines, there was a tendency of higher expression of MHC class I on Vemurafenib resistant cell lines. BRAF exon15 sequencing shows no difference between Vemurafenib resistant and sensitive cell types. Experiments are in progress to understand the mechanism(s) of the reduced sensitivity of the Vemurafenib resistant cell lines to NK cell killing.
Targeted molecular therapies for cancer: collateral damage? (P2028)
Authors: Allegrezza Michael , Rutkowski Melanie , Stephen Tom , Svoronos Nikos , Tesone Amelia , Conejo-Garcia Jose 
Published: January 2023

Abstract
Much attention has been given to the idea of personalized cancer treatment, where the oncogenes driving tumor growth can be identified in each patient and targeted with specific molecular therapies. Many targeted inhibitors are in clinical development after showing promise in xenograft tumor models, but their impact on anti-tumor immunity remains unknown. Because immune cells use many of the same pathways frequently mutated in cancer (MAPK, PI3K, CDK), we hypothesized that molecular inhibition of these pathways would also detrimentally affect anti-tumor immunity. We tested a panel of over 40 molecular inhibitors on TCR-induced proliferation of human T cells and found that many of these inhibited proliferation at active concentrations nearly identical to those found when tested against tumor cells. Further analysis with PI3K and MEK inhibitors showed that their effect on T cell function varied depending on the stimulation strength and presence of certain cytokines. These findings indicate that many of these molecules may be immunosuppressive, and this knowledge can help guide the development of therapies that inhibit tumor cells while maintaining protective anti-tumor immunity in order to achieve maximum therapeutic effects.
Immunotherapy of disseminated intraperitoneal pancreatic cancer with non-replicating Toxoplasma gondii (P2104)
Authors: Sanders Kiah , Fox Barbara , Bzik David 
Published: January 2023

Abstract
Pancreatic cancer is one of the most devastating and deadly cancers with an overall 5-year survival rate of 5%. Given existing therapies offer limited benefit, there is a strong need for innovative treatments that boost the host immune response to cancer. Toxoplasma gondii is an obligate intracellular parasite that potently stimulates the immune system and elicits CD8 T cell dependent immune responses. Utilizing an intraperitoneal dissemination model of pancreatic cancer, we hypothesize a non-replicating strain of T. gondii (CPS) can alter the tumor microenvironment and elicit strong antitumor responses. Intraperitoneal PAN02 tumors were established and treated with CPS seven days later. CPS treatment significantly increased survival and some treated mice survived long term (&gt;1 year). Treatment efficacy was completely dependent on production of IL-12 and IFN-γ. Within the peritoneal exudate, there is a significant decrease in B cells and classical macrophages and a significant increase in neutrophils, CD4, and CD8 T cells compared to untreated tumors. Therapeutic benefit was dependent on the presence of CD8 T cells whereas CD4 T cells did not significantly contribute to the survival advantage in treated mice. CPS treatment increased the frequency of pancreatic tumor-specific IFN-γ producing CD8 T cells. Further investigation is needed to characterize innate immune mechanisms supporting tumor therapy as well as the potential induction of immune memory.
NKT cells as a novel platform for cancer immunotherapy with chimeric antigen receptors (P2038)
Authors: Heczey Andras , Liu Daofeng , Courtney Amy , Marinova Ekaterina , Wei Jie , Tian Gengwen , Yvon Eric , Hicks John , Dotti Gianpietro , Metelitsa Leonid 
Published: January 2023

Abstract
Transgenic expression of chimeric antigen receptors (CARs) in primary T cells is an attractive strategy for cancer immunotherapy. However, poor homing of CAR T cells to the tumor site limits their therapeutic potential. Because Vα24-invariant Natural Killer T cells (NKTs) naturally localize to solid tumors, we examined their ability to serve as a cellular carrier for anti-tumor CARs. We genetically modified primary human NKTs to express a CAR against GD2 ganglioside, which is highly expressed in tumors of neuroectodermal origin such as neuroblastoma or melanoma. CAR expression rendered NKTs highly cytotoxic against GD2-positive neuroblastoma cells without affecting their native CD1d-restricted reactivity. The comparison of CAR constructs encoding different co-stimulatory endodomains revealed a striking Th2-like or Th1-like polarization of NKTs by CARs with CD28 or CD137, respectively. CAR NKTs had potent and long-lasting anti-tumor activity in a metastatic model of neuroblastoma in humanized NOD/SCID/IL-2γ(null) mice. Furthermore, in contrast to CAR T cells from the same donor, CAR NKTs did not induce graft-versus-host disease. These results establish the potential of NKTs to serve as an effective cellular platform for anti-tumor CAR therapy.
Integrin alpha 4 differentially affect the migration of effector and regulatory T cells (P4113)
Authors: Bettelli Estelle , Glatigny Simon , Duhen Rebekka , Arbelaez Carlos , Kumari Swarnima , Oukka Mohamed , Bettelli Estelle 
Published: January 2023

Abstract
The integrin alpha 4 (Itga4) is expressed on immune cells and is an important molecule for the migration of T cells in various organs. Because of this propriety, a monoclonal antibody specific to Itga4 is used for the treatment of multiple sclerosis (MS). Although effective, anti-Itga4 therapy has been associated with the development of progressive multifocal leukoencephalopathy (PML), a life threatening condition, which results from a rare infection of the central nervous system (CNS) by the JC virus. Despite its use and efficacy in the clinic, it remains unclear how different cells of the adaptive immune system are affected by Itga4 deletion or neutralization. Experimental autoimmune encephalomyelitis (EAE) serves as an animal model of multiple sclerosis (MS). It results from an autoimmune attack by myelin reactive effector T helper (Th) 1 and Th17 cells and progressive demyelination. Foxp3+ regulatory T cells can control effector T cell responses but are not always effective during autoimmune disease progression. Using mice with selective deletion of Itga4 in T cells, we previously reported that Itga4 selectively inhibits the migration of Th 1 cells but not Th17 cells in the CNS. We have now established that Itga4 differentially affect the migration of effector and regulatory T cells during EAE. The implication of our findings for MS therapy will be discussed.
Pathogenesis of Systemic Lupus Erythematosus and aiCD4 T cell: new insight on autoimmunity (P4121)
Authors: Shiozawa Shunichi , Miyazaki Yumi , Tsumiyama Ken 
Published: January 2023

Abstract
A question in the pathogenesis of autoimmunity is why and how autoreactive lymphocytes survive beyond the firewall of immunity. According to the autoimmune disease theory, autoreactive lymphocytes derive from either a few autoreactive clones that escape from thymic negative selection or those reactivated from tolerance. Such restricted clones apparently do not represent wide varieties of TCR repertoire or autoantibody of more than 100 distinct specificities seen in SLE. We instead show that autoreactive clones newly emerge via de novo TCRα, but not TCRβ, revision at periphery from thymus-passed non-autoreactive clones. We name this novel T cell type an autoantibody-inducing CD4 T cell (aiCD4 T cell), which stimulates B cells to generate varieties of autoantibodies and also helps final differentiation of CD8 T cell into CTL via antigen cross-presentation to induce lupus tissue injuries. Our life is a continuous battle against pathogen: host dies if pathogen is too strong due to pathogen-induced tissue injury and the host also dies if defense is too strong due to defense-induced injury, because battle field is our body. To avoid exhaustive battle, our immunity evolved not to eradicate but just suppress pathogen to undersea levels. Thus, repeated exposure to antigen is not exceptional but routine. SLE necessarily emerges when host’s immune system is overstimulated by repeated exposure to pathogen to levels that surpass system’s stability-limit: self-organized criticality theory.
Analyzing the contributions of TCR affinity to the pathogenesis of experimental autoimmune encephalomyelitis (P4129)
Authors: Blanchfield J. Lori , Bettini Maria , Vignali Dario , Evavold Brian 
Published: January 2023

Abstract
Myelin oligodendrocyte glycoprotein (MOG) specific CD4+ T cell infiltrates from the central nervous system (CNS) have exhibited a range of affinities (low to high) for MOG peptide:MHC class II during peak EAE symptoms. Tetramer binding analyses and two-dimensional affinity assays have indicated that high affinity, MOG specific T cells comprise a rare yet significant population within the polyclonal repertoire; however, their functional contributions to the pathogenesis of chronic autoimmunity is not clear. Preliminary experiments suggested that a high precursor frequency (15 x 106) of polyclonal tetramer positive MOG specific T cells promotes early onset and greater disease severity when compared to tetramer negative T cells. Analysis of a high affinity MOG specific, CD4+ T cell (TCR Vα4β1) revealed a two dimensional affinity of 6.4x10-4 μm4 that was similar to the mean affinity (1.6x10-4 μm4) of pathogenic CD4+ T cells at peak LCMV Armstrong infection. Retrogenic models were used to assess the pathogenicity of TCR affinity in order to circumvent the limited number of endogenous high affinity T cells. The TCR Vα4β1 retrogenic mice developed spontaneous EAE even in the presence of FoxP3 positive (6%) T cells. T cells progressed though thymic selection without altering CD4 or TCR expression while maintaining their high two-dimensional affinity. Overall, MOG specific, high affinity CD4+ T cells are pathogenic and may predispose mice to a rapid progressive course of EAE.
Enhanced PI3K/Akt-mediated survival of memory Th1 cells in type-1 diabetics and healthy controls carrying the autoimmunity-associated 1858T allelic variant of PTPN22 (P4097)
Authors: Turner Michael , Habib Tania , Rieck Mary , Funk Andrew , Anderson Warren , Puri Kamal , Buckner Jane 
Published: January 2023

Abstract
A C-to-T polymorphism (1858T) in the PTPN22 gene alters the function of the lymphoid phosphatase Lyp and confers increased risk for autoimmunity. The PTPN22 1858T allele is associated with altered TCR signaling and expanded memory T cell pool. To determine its impact on lineage commitment and survival, naïve CD4+ T cells from healthy subjects carrying risk or non-risk alleles were differentiated in vitro. Cultures of T cells bearing PTPN22 1858T displayed similar proliferative capacity but reduced activation-induced cell death, yielding more IFNγ+ Th1 cells than non-risk controls. In vivo, PTPN22 1858T subjects mounted enhanced IFNγ responses to the pneumococcal vaccine Prevnar, but not IL-2 production or T cell proliferation. Examination of TCR-mediated signaling revealed that elevated pAkt activity and BCL2 expression were associated with the PTPN22 1858T allele and correlated with enhanced T cell survival during in vitro stimulation. This phenotype was mirrored in T cell cultures from type-1 diabetic subjects, regardless of their PTPN22 genotype, and was reversed by a PI3Kδ-specific inhibitor. Our studies indicate that the autoimmunity-associated PTPN22 1858T allele protects T cells from apoptosis via elevated PI3K/Akt signaling, leading to the accumulation of pro-inflammatory memory Th1 cells. This T-cell intrinsic defect is a general feature of T1D and inhibition of PI3Kδ offers a potential avenue for pharmacological intervention.
The TGFβ-activating integrin αvβ8 on dendritic cells regulates type 2 immunity in the intestine to promote chronic parasitic infection (P3318)
Authors: Worthington John , Klementowicz Joanna , Rahman Sayema , Czajkowska Beata , Waldmann Herman , Sparwasser Tim , Grencis Richard , Travis Mark 
Published: January 2023

Abstract
The cytokine TGFβ is crucial in regulating immunity in the intestine, but its role and regulation during responses to intestinal infection is not well understood. We therefore addressed how TGFβ functions and is controlled during chronic intestinal infection, using the model murine parasite Trichuris muris (the human homologue of which affects ~600 million people world-wide, causing severe health problems). We found that TGFβ signalling is induced early during infection, specifically in CD4+ T-cells. This enhanced signalling involves expression of the TGFβ-activating integrin αvβ8 by dendritic cells (DCs). Importantly, mice lacking integrin αvβ8 on DCs are completely resistant to chronic infection with T. muris, indicating an important functional role for integrin αvβ8-mediated TGFβ activation in promoting chronic infection. Protection from infection is dependent on CD4+ T-cells, but is independent of Foxp3+ Tregs as mice depleted of Foxp3+ Tregs during infection remained susceptible to infection. Instead, lack of integrin αvβ8 on DCs led to an early increase in expression of the Th2 cytokine IL-13 by CD4+ T-cells which is required for protection from infection. Our results therefore provide novel insights into how type 2 immunity is controlled in the intestine during gastrointestinal parasite infection, and may help contribute to the development of new therapies aimed at promoting expulsion of gut parasites.
MHC II restricted CD3+CD4-CD8- cells display functional characteristics of memory cells and contribute to optimal secondary immunity to Leishmania major in mice (P3337)
Authors: Uzonna Jude , Mou Zhirong , Okwor Ifeoma , Liu Dong , Jia Ping 
Published: January 2023

Abstract
Although it is generally believed that CD4+ T cells play important role in anti-Leishmania immunity, some studies suggest that they may be dispensable and MHC II-restricted CD3+CD4-CD8- T (double negative, DN) cells may be more important in regulating anti-Leishmania immunity. Indeed, expansion of DN cells occurs in the blood of infected patients and dogs, and in spleens of infected mice and has been proposed to contribute to immunity against Leishmania. However, concrete evidence implicating DN cells in anti-Leishmania immunity is lacking. Here, we show that following primary L. major infection, DN cells in lymphoid organs of infected mice are activated, proliferate and produce IFN-γ. Furthermore, DN cells from mice that healed their primary L. major infection display functional characteristics of anti-Leishmania memory-like cells: they rapidly and extensively proliferate and produce IFN-γ in response to L. major challenge in vitro and in vivo. Interestingly, DN cells express alpha-beta T cell receptor (αβ TCR), and are restricted by MHC class II molecules. Moreover, DN cells from healed mice, but not those from naïve mice, control parasite growth in infected macrophages in vitro. Using in vivo depletion and adoptive transfer studies, we show that DN cells from healed mice contribute to optimal secondary anti-Leishmania immunity in mice. These results demonstrate that CD3+CD4-CD8- cells play a role in both primary and secondary (memory) anti-L. major infection.