bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-PDL-1 immunotherapy alters T cell anti-tumor responses and inhibits tumor progression in the lung (162.13)
Authors: Bartkowiak Todd , Zal Tomasz 
Published: January 2023

Abstract
Lung cancer is the second most common form of cancer-behind prostate cancer in men, and breast cancer in women-accounting for 15% of all new cases. It is also the leading cause of death among both men and women. Secondary lung cancer is also an important problem which arises from primary tumors in other tissues aggressively metastasizing to the lungs. The lung is a key site of tumor metastasis, and these secondary tumors are very difficult to treat. Treatment of lung cancer is typically invasive and ranges from chemotherapy, to radiotherapy, to surgical removal of the cancerous tissue. However, a new horizon of cancer therapy involves immunotherapy--altering and/or boosting the immune system to help fight cancer. One immune-targeted cancer therapy involves blocking the PD1/PDL1 pathway; a pathway which acts to suppress the immune system by inhibiting T cell signaling. However, little is known about how exactly this and other immunotherapies modulate anti-tumor T cell responses in vivo. We used confocal and multiphoton microscopy to track T cell motility and T cell/tumor interactions in vivo within lung tumors in PDL-1 treated mice. Blockade of PDL-1 altered the spatio-temporal patterning of T cell motility and their tumor killing power, and inhibited lung tumor progression. The knowledge of how αPDL-1 cancer immunotherapy affects the immune microenvironment of tumors can lead to the development of safer, more potent treatments for lung cancer and other forms of cancer.
Role of PI3K-Akt in crosstalk between Notch and CD28-CD80/86 pathways in dendritic cell “backsignaling” (162.2)
Authors: Koorella Chandana , Nair Jayakumar , Carlson Louise , Lee Kelvin 
Published: January 2023

Abstract
Survival of myeloma cells is characterized by their interaction with bone marrow stromal cells, which produce critical soluble factors including IL-6 and IDO. Targeting pathways involved in production of factors which are important in myeloma cell biology, provides novel therapeutic targets for a disease which otherwise remains incurable. At the cellular level, dendritic cells (DC) in the bone marrow microenvironment and at the molecular level the CD28-CD80/86 and Notch-Jagged pathways were separately implicated by us in myeloma induced IL-6 production. While Notch signaling leading to IL-6 production in DC is well understood, the mechanism of “backsignaling” via CD80/86- ligands with short cytoplasmic tails, remains largely uncharacterized. We demonstrate that inhibiting Notch signaling leads to a significant decrease in CD28 mediated IL-6 and IDO production by DC, suggesting crosstalk between Notch and CD28-CD80/86 pathways. IL-6 production by dendritic cells, upon ligation of CD80/86 by CD28-Ig, involves the PI3K-Akt-FoxO3a axis, which has not been previously established. Furthermore, we demonstrate a novel crosstalk between Notch and CD80/86 signaling involving regulation of the PI3K-Akt pathway by casein kinase and PTEN, which in turn are regulated by Notch signaling. Targeting pathways involved in IL-6 and IDO prompts not only clinical evaluation to improve MM patient outcome but also extends to advancing knowledge in T-cells and normal plasma cell biology.
Synapse-directed delivery of immune-stimulants using T-cell-conjugated nanoparticles (162.30)
Authors: Stephan Matthias , Bak S. , Stephan Sirkka , Chen Jianzhu , Irvine Darrell 
Published: January 2023

Abstract
Regulating molecular interactions in the T cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T cell membrane proteins enables efficient delivery of compounds into the T cell synapse. We demonstrate that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T cell/APC contact zone during antigen recognition. To translate these findings into a novel therapeutic application we tested the NP delivery of NSC-87877, a dual inhibitor of Shp1 and Shp2, key phosphatases that downregulate T cell receptor activation in the synapse, in the context of adoptive T cell therapy of cancer. Conjugating NSC-97977-loaded NPs to the surface of tumor-specific T cells just prior to adoptive transfer into mice with advanced prostate cancer greatly promoted T cell expansion at the tumor site, relative to co-infusing the same drug dose systemically, leading to enhanced survival of treated animals. Altogether, our studies support the application of T-cell-linked synthetic NPs as efficient drug delivery vehicles into the IS, as well the broad applicability of this new paradigm for therapeutically modulating signaling events at the T-cell/APC interface.
The importance of type I interferons in radiation-mediated antitumor responses (162.33)
Authors: Lim Joanne , Gerber Scott , Lord Edith 
Published: January 2023

Abstract
Interferon alpha (IFNα) has been FDA-approved for treatment of high-risk melanoma since 1995. Besides having direct antitumor effects, IFNα and IFNβ, the other major type I IFN (IFN-I), have been found to act through enhancing multiple pathways within the host immune system. However, the mechanisms by which IFN-Is mediate these responses remain unclear. Our previous data demonstrated that treatment of in vivo B16 melanoma with a single high dose local radiation induced an increase in IFNγ levels within the tumor microenvironment. Interestingly, this increase is abolished in the absence of IFNα/β signaling within host cells, as observed using IFNα/β receptor knockout mice (KO). Importantly, the induction of downstream IFNγ-dependent genes such as the CXCR3 family of chemokines is also affected. Since CXCR3 chemokines have been shown to be crucial chemoattractants for T cells in tumors, it is not surprising that the lack of IFNα/β receptor also resulted in decreased recruitment of CD8 T cells to tumors in response to radiation treatment. Corresponding to these effects, radiation-treated KO mice exhibit poor tumor growth control compared to wild type mice. Taken together, our data suggest that IFN-Is play a critical role in radiation-mediated antitumor responses. An important mechanism through which this occurs depends on the ability of IFN-Is to enhance IFNγ responses, which in turn upregulates CXCR3 chemokines in the tumor, resulting in enhanced recruitment of CD8 T cells.
Immunoglobulin Fc fragment tagging allows strong activation of endogenous CD4 T cells to re-shape the tumor milieu and enhance the antitumor effect of lentivector immunization (162.4)
Authors: He Yukai , Hong Yuan , Peng Yibing , Xiao Haiyan , Mi Michael , Munn David 
Published: January 2023

Abstract
A major problem with current cancer vaccines is that the induction of CD8 immune responses is rarely associated with antitumor benefits mainly due to the multiple immune suppressions in the established tumor lesions. In this study, we investigated if and how activation of endogenous CD4 T cells could be achieved to relieve the suppressive tumor milieu. We engineered a lentivector to express a nominal fusion Ag composed of HBsAg and IgG2a Fc fragment (HBS-Fc-lv) to increase the magnitude of CD8 response, but more importantly, to induce effective CD4 co-activation. We found that, remarkably, HBS-Fc-lv immunization caused significant regression of established tumors. Immunological analysis revealed that HBS-Fc-lv immunization markedly increased the number of functional CD8 and CD4 T cells and the level of Th1/Tc1-like cytokines in the tumor, while substantially decreased Treg ratio. The favorable immunologic changes in tumor lesions and the improvement of antitumor effects from HBS-Fc-lv immunization were dependent on the Fc receptor mediated CD4 activation. Adoptive transfer of the CD4 T cells from the HBS-Fc-lv immunized mice could activate endogenous CD8 T cells via IFNgamma and CD40L dependent manner. We conclude that endogenous CD4 T cells can be activated by lentivector expressing Fc tagged Ag to provide another layer of help, i.e. creating a pro-inflammatory milieu within the tumor lesion to help the effector phase of immune responses to enhance the antitumor effect.
Aire regulates immune tolerance towards melanoma (162.43)
Authors: Zhu Menglei , Nagavall Anil , Su Maureen 
Published: January 2023

Abstract
Effective recognition of tumor antigens by circulating T cells constitutes an important part of successful immunosurveillance against cancer growth. Immune tolerance towards tumor antigens, therefore, is a barrier toward an effective anti-tumor immune response. Autoimmune regulator (Aire) is a transcriptional regulator that is critical for the development of central T cell tolerance by inducing self-antigen expression in the thymus. Aire has a well-known role in preventing autoimmunity, and Aire deficiency leads to multi-organ autoimmunity in both human patients and mice. Recently, Aire polymorphisms have been shown to be associated with melanoma development. Whether Aire may mediate immune responses against tumors and its mechanism, however, is not clear. We utilized a mouse harboring a dominant negative point mutation in Aire (Aire G228W) that results in hypomorphic Aire function to investigate the role of Aire deficiency in melanoma. Aire G228W mice develop more robust immune response against melanoma which leads to suppressed tumor growth. This enhanced immune response results from defective negative selection of T cells recognizing melanoma. Aire expression in the thymus is sufficient to mediate immune tolerance against melanoma. Our findings provide a biological mechanism for the epidemiological association between Aire polymorphisms and risk for melanoma and suggest that modulation of central tolerance mechanisms could be a potential strategy for cancer therapy.
Inhibition of prostate tumor growth by potentiating antitumor immune response using natural product (162.46)
Authors: Singh Shailesh , Singh Rajesh , Lillard, Jr. James , Grizzle William 
Published: January 2023

Abstract
It is now well accepted that tumors evade the patient's defense system during progression and growth at distant sites. Mounting evidences suggest immunological defects in PCa patients with higher numbers of functionally suppressive CD4+CD25+FOXP3+ T cells (Treg) and lower number of effectors T cells. Furthermore, tumor microenvironment exerts a profound immunosuppressive effect on effectors T cells by secreting TGF-β and IL-10. Therefore, modulating TGF-β and IL-10 using natural and dietary components constitutes an innovative approach for prostate cancer prevention and treatment. In this study, we have shown that Withaferin-A (WA), a bioactive compound isolated from Withania Somnifera also called “Ashwagandha” has the ability to modulate immunosuppressive cytokines (IL-10 and TGF-β) produced by the PCa cells. Additionally, we show selective inhibition of Treg proliferation and induction of apoptosis in Tregs cells in immune competent PCa mouse model treated with WA compared to controls. Our results suggest that WA have potential to fine-tune immunosuppressive phenotype of tumor-associated lymphocytes by modulating immuno-suppressive cytokines. Significant inhibition of tumor growth in immune competent PCa mouse model as compared to immune deficient xenograft suggest potential role of WA on reversal of anti-tumor immune response from immune suppression to immune competence, which is required to fight against prostate cancer.
Regulation of SHP2 by PTEN/AKT/GSK-3β signaling facilitates IFN-γ resistance in hyperproliferating gastric cancer (162.8)
Authors: Tseng Po-Chun , Huang Wei-Ching , Chen Chia-Ling , Sheu Bor-Shyang , Shan Yan-Shen , Tsai Cheng-Chieh , Wang Chi-Yun , Chen Su-O , Hsieh Chia-Yuan , Lin Chiou-Feng 
Published: January 2023

Abstract
In addition to oncogenic activation, and tumor suppressor gene inactivation escape from immune surveillance, such as IFN-γ resistance, is critical for cancer cell growth and survival. In this study, we investigated the crosstalk signaling between IFN-γ resistance and signaling of hyperproliferation in gastric cancer cells. IFN-γ inhibited the cell growth of MKN45 cells but not hyperproliferating AGS cells. AGS cells did not respond to IFN-γ because of a decrease in STAT1 but not due to dysfunctional IFN-γ receptors. Signaling of PI3K/AKT, as well as MEK/ERK, was required for the hyperproliferation; notably, PI3K/AKT alone mediated the IFN-γ resistance. Aberrant Src homology-2 domain-containing phosphatase (SHP) 2 determined IFN-γ resistance but unexpectedly had no effects on hyperproliferation or ERK activation. In the IFN-γ resistant cells, inactivation of glycogen synthase kinase (GSK)-3β by PI3K/AKT was important for SHP2 activation but not for hyperproliferation. An imbalance of AKT/GSK-3β/SHP2 caused by a reduction of PTEN was important for the crosstalk between IFN-γ resistance and hyperproliferation. PI3K is constitutively expressed in AGS cells and immunohistochemical staining showed a correlation between hyperproliferation and expression of SHP2 and STAT1 in gastric tumors. These results demonstrate the effects of PTEN/AKT/GSK-3β/SHP2 signaling on IFN-γ resistance in hyperproliferating gastric cancer cells.
The generation of TH17 cells in response to bacterial infection requires IL-6 and dendritic cell-produced TGF-β1, but not IL-1 (163.14)
Authors: Linehan Jonathan , Dileepan Thamotharampillai , Cleary P. , Jenkins Marc 
Published: January 2023

Abstract
Whether TGF-β1, IL-1, and IL-6 are required for TH17 cell development and maintenance in vivo remains controversial. For example, a recent study suggested that TGF-β1 is not necessary for TH17 differentiation, whereas another proposed that a T cell-derived source is required. Other studies have implicated varying roles for IL-1 and IL-6 in TH17 differentiation as well. We investigated the requirement for TGF-β1, IL-1, and IL-6 in TH17 differentiation using tetramers of peptide and major histocompatibility complex II (pMHCII) to track an endogenous, pMHCII-specific TH17 response to intranasal infection with Streptococcus pyogenes. We show that TGF-β1 and IL-6 were absolutely necessary for TH17 differentiation in vivo, whereas IL-1 was dispensable. Additionally, deletion of the Tgfb1 gene from CD11c+ cells abrogated TH17 cell differentiation, while Tgfb1 deletion from T cells had no effect. These results identify an essential role for IL-6 and dendritic cell-produced TGF-β1 in promoting the differentiation of TH17 cells, during intranasal infection with a pathogen.
SLAM/ SAP signaling positively regulates the differentiation of TH17 cells and experimental autoimmune encephalitis (163.15)
Authors: Huang Yu-Hsuan , Chung Brian , Priatel John , Tan Rusung 
Published: January 2023

Abstract
Mutations in SAP (SLAM-associated protein) underlie the majority of cases of X-linked lymphoproliferative disease (XLP), a rare congenital disorder that often leads to fatal complications upon infection with Epstein-Barr virus. The small SH2-containing adaptor SAP transmits signaling via SLAM (signaling lymphocytic activation molecule) family receptors and has been shown to be critical for development and function of multiple immune cell types. Here, we have investigated the role of SLAM and SAP signaling in regulating the differentiation of naïve CD4 T cells into IL-17 secreting effectors (TH17 cells), a pro-inflammatory lineage implicated in host defense as well as autoimmune diseases. T cell receptor activation along with co-stimulating SLAM antibodies was found to augment TH17 cell differentiation in wild type but not SAP-deficient splenic T cells under IL-17 polarizing conditions. Furthermore, SAP-/- mice were protected from experimental autoimmune encephalomyelitis (EAE), exhibiting greatly decreased numbers of CNS-infiltrating TH17 cells and dramatically reduced disease severity. Collectively, these results suggest that SLAM-SAP interactions promote the differentiation of IL-17 secreting effector CD4 T cells both in vitro and in vivo.
Metabolic control of T cell fate decision: the HIF1α-glycolysis axis in the differentiation of TH17 and iTreg cells (163.17)
Authors: Shi Lewis Zhichang , Wang Ruoning , Green Douglas , Chi Hongbo 
Published: January 2023

Abstract
Activated T cells mainly use glycolysis to suffice their bioenergetic and biosynthetic demands. However, whether glycolysis actively controls the differentiation of activated T cell is not fully understood. As a master regulator of metabolism, HIF1α regulates multiple rate-limiting glycolytic enzymes. We previously reported that HIF1α deficiency inhibited TH17 differentiation and promoted induced Treg (iTreg) generation (Shi et al, J Exp Med 2011). To further explore the roles of the glycolytic pathway in T cell differentiation, we combined genetic and pharmacological approaches to examine T cell metabolism and signaling. Inhibition of glycolysis by multiple agents diminished TH17 differentiation and promoted iTreg induction, while supplementation of the products of the glycolytic flux partially rescued these defects. Importantly, blocking glycolysis ameliorated the pathogenesis of autoimmune neuroinflammation both prophylactically and therapeutically, suggesting that the glycolytic pathway is a potential therapeutic target for autoimmune pathogenesis elicited by TH17 cells. Mechanistic studies further revealed that downregulation of IL-23R expression contributed to the diminished TH17 differentiation in HIF1α-deficient T cells, as forced expression of IL-23R restored the TH17 defects. In conclusion, our results demonstrate that the HIF1α-mediated glycolytic pathway links T cell metabolism and signaling, thereby dictating the cell fate decision between TH17 and iTreg cells.
Complex role for IL-2 Inducible T cell kinase (Itk) in T helper 1 and T helper 2 differentiation and function (163.18)
Authors: Kannan Arun , Sahu Nisebeta , August Avery 
Published: January 2023

Abstract
T helper responses are critical for a productive immune response but an inappropriate response results in inflammatory and autoimmune disorders. There are still considerable gaps in our knowledge of pathways that regulate differentiation of T helper subsets. IL-2 Inducible T cell kinase (Itk) is primarily expressed in T cells and is critical for their development, activation and function. Here, we show that Itk regulates two distinct signals during T helper differentiation. The first signal represses IFNγ independent of Tbet and maintains naïve T cells in an unbiased state, until it comes in contact with cognate antigen. This signal controls epigenetic processes that maintains the IFNγ locus closed and is critical for induction of Th2 transcriptional program. The second signal occurs following T cell activation, and is critical for secretion of Th1, Th2 and Th17 cytokines. As a result, Itk-/- mice are not only defective in Th2 responses, but are also more susceptible to infection by Th1 inducing intracellular pathogen T. Gondii. More importantly, these signaling pathways are conserved in humans, as loss of Itk in human PBMC derived T cells and Jurkat cells results in a substantial reduction in the secretion of a number of effector cytokines, at least partly due to a failure to activate pERK. This work has implications for understanding T helper differentiation programs, and Itk as a therapeutic target for Th2 mediated inflammatory and Th1/ Th17 mediated autoimmune disorders
A proteomic study of early signaling events regulating the Fas-FasL Death Inducing Signaling Complex (163.20)
Authors: Ramaswamy Madhu , Do Thao , Barden Mary , Cruz Anthony , Siegel Richard 
Published: January 2023

Abstract
Clearance of activated T cells by the Fas-FasL pathway is a critical mechanism of peripheral CD4 T cell tolerance. This process is preferentially higher in the effector subset of memory CD4+ T cells due to efficient recruitment and formation of the Fas death inducing signaling complex (DISC). In order to elucidate mechanisms of this heightened apoptosis sensitivity, we tested for differential DISC interacting proteins in Fas sensitive and Fas resistant CTCL cell lines using 2D-DIGE and Mass Spectrometry. We found several candidate proteins and invitro studies were done to confirm Fas receptor interactions through overexpression and Flourescence Energy Transfer (FRET) studies. One of these targets, Drebrin, is an actin binding protein previously found to play a role in T cell synapse formation by facilitating CXCR4 recruitment. Overexpression in 293 indicates that Drebrin interacts with Fas receptor. Further, endogenous drebrin preassociates with Fas receptor and remains associated with the Fas DISC even after Fas ligation only in Type I SKW cell line. Interestingly, Fas DISC associated Drebrin gets cleaved after Fas treatment and invitro caspase cleavage studies indicate that drebrin is a specific downstream target of caspase-8. Our studies propose Drebrin as a novel Fas interacting protein. Investigations are currently underway to study the mechanisms by which Drebrin modifies the Fas-DISC dynamics and the significance of the caspase-cleaved Drebrin in this process.
Effect of Selective Aryl Hydrocarbon Receptor Modulators on a murine model of Th17 driven Hypersensitivity Pneumonitis (HP) (163.21)
Authors: Mohinta Sonia , Perdew Gary , August Avery 
Published: January 2023

Abstract
The physiological role of Aryl Hydrocarbon Receptor (AhR) in immune response remains a key question after the discovery that AhR is an essential transcription factor for Th17 differentiation. To study the role of AhR in T cell differentiation we examined the effects of Selective AhR Modulators (SAhRMs) on antigen specific T cell response in vitro. We found that as expected, an AhR agonist enhances IL-17A production whereas a SAhRM suppresses it. However, we also found that AhR agonists suppressed production of IL-4, which was induced by the SAhRM. By contrast IFNγ was inhibited by both compounds. We also examined the effect of SAhRMs on a well established Th17 driven murine model of hypersensitivity pneumonitis mediated by a thermophile Staphylopolyspora rectivirgula (SR). Treatment of mice that have developed SR driven airway inflammation with an AhR partial antagonist or an antagonist, suppressed AhR activation in the lung. However, these AhR ligands also increased the production IL-4 by T cells in the lung, with an increase in the percentage of T cells that produce both IL-17A and IL-4. By contrast, these ligands did not suppress IFNγ or IL-17A production. Analysis of cytokine transcripts in lungs confirmed these data. This suggests that although AhR activation is required for Th17 differentiation, once cells commit to Th17 lineage, inhibiting AhR may not affect Th17 cytokine production, but may enhance the ability of these cells to produce IL-4.