bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of non-HLA antigens in cardiac transplant rejection
Authors: Panicker Anjali Jacob , Gates Katherine V , Biendarra-Tiegs Sherri M , Vetr Nikolai G , Higuita Manuela Lopera , Nelson Timothy J , Pereira Naveen L , Griffiths Leigh G 
Published: January 2023

Abstract
Although immunosuppressive drugs improve short term survival, rejection incidence and long term survival remain largely unchanged in heart transplant patients. While Human Leukocyte Antigen (HLA) is a common initiator of graft-specific immune responses, non-HLA antibody mediated rejection (AMR) also commonly occurs. Furthermore, non-HLA antibodies have been implicated in cell mediated rejection and cardiac allograft vasculopathy. Therefore, there is a need to identify the role of non-HLA antigens in heart transplant rejection.
Serum from heart transplant patients lacking donor specific anti-HLA antibodies was collected longitudinally; pre-transplantation, acute rejection, and post-rejection for patients with AMR and matched controls. Serum IgG was used to form anti-human heart affinity columns and antigenic proteins from donor heart extracts captured. Antigens were eluted from the columns and subjected to LC-MS/MS. Longitudinal graft-specific changes in immune response were calculated.
Response toward non-HLA antigens increased longitudinally, with 41 high prevalence antigens found in ≥50% of the cohort. Co-culturing cardiomyocyte and endothelial cells with patient IgG indicated cell function changes correlated with specific antigens (e.g., Prohibitin). Immunofluorescence staining of patient biopsies revealed that longitudinal increase in antigen expression correlated with non-HLA antibody response.
The non-HLA antigens identified in this study elicit acute and chronic graft-specific adaptive immune responses in heart transplant recipients. Antibodies against these non-HLA antigens induced cellular dysfunction by changing expression of their target protein in the donor heart.
Enhancing IFN-β production through synergy between the STING pathway and TLR pathways
Authors: Higgs Emily , Gajewski Thomas 
Published: January 2023

Abstract
Previous work from our lab has shown that tumors activate the STING pathway in antigen presenting cells. STING signaling leads to IFN-β production which is required for T cell priming and recruitment. IFN-β transcription is induced by multiple transcription factors including NF-κB and IRF3. Enhancing STING activation and downstream IFN-β production has therapeutic potential, and STING agonists are currently being evaluated in clinical trials. However, innate immune activation in response to a pathogen rarely occurs by activating only one signaling pathway, and activating multiple innate immune pathways similar to a natural infection could improve the efficacy of STING agonists. To test this, we performed experiments with the STING agonist DMXAA alone or in combination with several TLR agonists. We found that LPS + DMXAA induced significantly greater IFN-β transcription than the sum of either agonist alone. To explain this synergy, we assayed each step of STING pathway signaling. LPS did not increase STING aggregation beyond that induced by DMXAA. Additionally, LPS did not increase IRF3 phosphorylation nor IRF3 nuclear translocation in combination with DMXAA. LPS did increase the phosphorylation and nuclear translocation of the NF-κB subunit p65. These results suggest that the synergy in IFN-β production is achieved through IRF3 activation downstream of STING signaling and NF-κB activation downstream of TLR4 signaling. Intratumoral injection of LPS + DMXAA resulted in significantly improved tumor control of B16 melanoma in vivo than either agonist alone, suggesting that combining activation of these pathways improves the anti-tumor innate immune response in a way that is therapeutically beneficial.
Expression of cancer cell-associated Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) regulates protective anti-tumor immunity in melanoma
Authors: Mandula Jessica , Mohamed Eslam , Sierra-Mondragon Rosa , Cao Yu , Trillo-Tinoco Jimena , Rodriguez Paulo 
Published: January 2023

Abstract
Activation of moderated endoplasmic reticulum (ER) stress in cancer cells promotes cellular adaptation and survival in response to the adverse conditions of the tumor microenvironment (TME). However, how modulation of ER stress in cancer cells culminates in the development of an immunosuppressive TME remains poorly understood and therapeutically unexploited. Upon disruption of ER homeostasis, mediator proteins IRE1a, ATF6 and PERK induce activation of the unfolded protein response (UPR). Although maladaptive priming of UPR mediators in immune cells deactivates their capacity for anti-tumor immunity, the immunosuppressive potential of UPR mediators in cancer cells, in particular PERK, remains unknown. Thus, in this study, we hypothesized that activation of PERK in tumor cells shapes the formation of the immunosuppressive TME and impairs the development of anti-tumor immunity. Elimination of PERK in cancer cells impaired survival upon chemically-induced ER stress and promoted caspase-independent cell death. Interestingly, in vivo ablation of PERK in melanoma impaired tumor growth, which surprisingly occurred in a T cell-dependent manner. Additionally we observed that ablation of PERK shifted the TME from an immunosuppressive to immunostimulatory environment, enhanced accumulation of effector T cells and directed reprogramming of myeloid derived suppressor cells (MDSCs) into immunostimulatory cells. Additional experiments indicated that ablation of PERK induced expression of mediators associated with immunogenic cell death. Collectively, our findings demonstrate the immunoregulatory role of PERK in tumor cells and highlight the therapeutic potential of targeting UPR mediators and tumor adaptive processes.
Too Much of a Good Thing: IFN-I, Dendritic Cells, and Cancer
Authors: Vartabedian Vincent F , Kemper Esther K , Parker Christopher G , Shaabani Namir , Teijaro John R 
Published: January 2023

Abstract
To prime T cells to fight cancer, dendritic cells (DCs) require Type I Interferon (IFN-I) signaling. IFN-I signaling induces the transcription and translation of Interferon Stimulated Genes (ISGs), including strong induction of Usp18, which dampens further IFN-I signaling. We hypothesized that increasing IFN-I signals to DCs in vivo via conditional Usp18 deletion would enhance the ability of DCs to prime T cells, augmenting their anti-tumor activity. To test this, we used Usp18fl/fl x CD11c-cre mice and the syngeneic B16F10 melanoma model. Surprisingly, tumors grew more quickly in Usp18fl/fl x CD11c-cre mice, and intratumoral T cells were less functional post-priming by Usp18-deficient DCs. This functional decrease was coupled with an accelerated effector differentiation marked by early loss of the stem cell-like factor TCF-1. These data suggest that Usp18-deficient DCs expedite terminal effector T cell differentiation, resulting in suppressed effector functionality at later time points. Consistent with this T cell dysfunction, intratumoral STING agonism was less effective at controlling tumors in Usp18fl/fl x CD11c-Cre mice than Usp18fl/fl littermate controls. To understand the molecular drivers of these changes, we profiled DCs with tandem mass tag (TMT) mass spectrometry. We found that Usp18-deficient DCs exhibit deficiencies in mitochondrial function and cysteine biosynthesis, potentially driving their altered ability to prime T cells. Overall, this work highlights the importance of stringent IFN-I signaling regulation for mounting optimal immune responses to cancer. Our findings also identify DC-intrinsic Usp18 expression as a potential biomarker for predicting patient responsiveness to STING agonist therapy.
T cells redirected against Igβ for the immunotherapy of B cell lymphoma
Authors: Jiang Dongpeng , Chu Jianhong , Wu Depei 
Published: January 2023

Abstract
CD19-redirected CAR-T immunotherapy has emerged as a promising strategy for treatment of B cell lymphoma, however, many patients often relapsed due to antigen loss. Therefore, it is urgently needed to explore other suitable antigens targeted by CAR-T cells to cure B cell lymphoma. Igβ is highly expressed on the surface of lymphoma cells and mutates in part of patients resulting continuous PI3K signaling promote the survival of B lymphoma. These conclusions suggest that wild-type or mutant Igβ may become a potential therapeutic target. In this study, we engineered T cells to express anti-Igβ CAR with CD28 costimulatory signaling moiety and observed that Igβ-CAR T cells could efficiently recognize and eliminate wild-type or mutant Igβ+ lymphoma cell lines both in vitro and in two different lymphoma xenograft models. Of note, both the in vitro and in vivo effect of Igβ CAR-T cells was comparable with that of CD19 CAR-T cells. Importantly, Igβ CAR-T cells recognized and eradicated patient-derived lymphoma cells in the autologous setting. Lastly, the safety of anti-Igβ CAR-T cells could be further enhanced by introduction of the inducible caspase-9 suicide gene system. Collectively, Igβ-specific CAR-T cells may be a promising immunotherapeutic approach for B cell lymphoma.
Myeloid-derived suppressor cell subset heterogeneity drives glioblastoma progression in a sex-dependent manner
Authors: Bayik Defne , Zhou Yadi , Park Chihyun , Hong Changjin , Vail Daniel , Silver Daniel J , Lauko Adam J , Roversi Gustavo A , Watson Dionysios C , Lo Alice , Alban Tyler J , McGraw Mary , Sorensen Mia D , Grabowski Matthew M , Otvos Balint , Vogelbaum Michael A , Horbinski Craig M , Khalil Ahmad M , Hwang Tae Hyun , Ahluwalia Manmeet S , Cheng Feixiong , Lathia Justin D 
Published: January 2023

Abstract
Immunosuppression is a major factor facilitating glioblastoma (GBM) progression and therapeutic resistance. We previously demonstrated that myeloid-derived suppressor cells (MDSCs) expand in GBM patients, but the mechanisms by which MDSC subsets promote tumorigenesis remain unknown. Using multiple syngeneic mouse GBM models, we show that monocytic MDSCs (mMDSCs) accumulate in tumors of males and associate with poor prognosis. Consistent with preclinical observations, males, who constitute 60% of GBM patients and have a worse prognosis than females, had significantly more tumor-infiltrating mMDSCs. In contrast, female tumor-bearing mice had a two-fold increase in circulating granulocytic MDSC (gMDSC) frequency, and a high gMDSC gene signature correlated with poor prognosis of female patients. Male-to-female bone marrow transplantation indicated that immune cell-intrinsic discrepancies drive the sex differences in GBM survival. In line with the differential MDSC localization, targeting gMDSCs with anti-Ly6G neutralizing antibodies extended the lifespan of female mice without affecting males. However, mMDSCs were protected from the anti-Ly6C depletion strategy due to their systemic and local proliferation, as indicated by ex vivo Ki-67 staining and subsequently confirmed by gene expression analysis. Drug-prediction using the differential expression profiles and subsequent pre-clinical testing established that mMDSCs can be targeted by chemotherapies, while IL-1 inhibitors are effective against gMDSCs. These findings indicate that MDSC subset variation represents an opportunity for improved immunotherapy efficacy while accounting for sex as a biological variable.
Dendritic cell dysfunction precedes tumor formation during pancreatic oncogenesis
Authors: Lin Jeffrey H , Vonderheide Robert H 
Published: January 2023

Abstract
Dysfunction of type 1 conventional dendritic cells (cDC1s) – the dendritic cell subtype crucial for spontaneous anti-tumor T cell immunity – has long been hypothesized to develop secondarily to invasive cancer. Here, we reveal that cDC1 dysfunction instead develops in the earliest stages of cancer development upon formation of preinvasive pancreatic intraepithelial neoplasias (PanINs) in the KrasG12D Trp53 R172H Pdx1-Cre-driven (KPC) mouse model of pancreatic ductal adenocarcinoma. This results in systemically increased cDC1 apoptosis and insufficient upregulation of T cell-polarizing cytokines during cDC1 maturation. CD8+ T cell activation following vaccination is subsequently impaired in PanIN- and tumor-bearing mice. Yet, combination therapy with CD40 agonist and Flt3 ligand in tumor-bearing mice returns cDC1 abundance to normal levels and induces an IFNg response signature, repairing cDC1 maturation and restoring full CD8+ T cell activation. This study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation while elaborating therapeutically tractable strategies towards cDC1 repair.
Distributions of non-expressed MHC class I chain related A (MICA) and NKG2D receptor polymorphism in cholangiocarcinoma
Authors: Phanabamrung Sornwit , Jumnainsong Amonrat , Leelayuwat Chanvit 
Published: January 2023

Abstract
MICA is an MHC class I like molecule functioning as a ligand of an activating receptor, NKG2D. This molecule is up regulated under stress conditions especially of cancerous cells. Thus, lacking of this molecule could lead to an impairment of immune surveillance and the progression of cancer. In addition to the ligand, polymorphism of NKG2D is also impact the activating function of immune cells. Thus, we have investigated the distributions of non-expressed (MICA*010) allele and deletion of the MICA gene in 365 northeastern Thais (NET) and 121 patients of cholangiocarcinoma (CCA) which is the most common form of intrahepatic cancer of NET with the highest prevalence in the world. MICA*010 and NKG2D typing were performed by PCR-SSP and the MICA deletion by multiplex PCR using three pairs of primers. The prevalence of MICA deletion was higher in CCA than that of NET (% allele frequency (%AF) of 0.25 vs 1.7: Pc = 0.036) with a relative risk of 6.21. Although the %AF of MICA*010 in CCA was not significantly different from NET (34.7 vs 34.3; p-value = 0.96), the prevalence of heterozygous MICA*010 with MICA null in CCA was significantly higher than that of NET (%AF = 0.29 VS 3; Pc = 0.037; RR = 3.39). The results suggested that individuals carrying the MICA null allele with or without the non-expressed allele were more susceptible to develop CCA implicating the involvement of immune escape via the activating receptor. Additionally, NKG2D polymorphisms were also investigated. These data will be combined with MICA results and discussed at the conference.
Distinct responses to αPD-1, αPD-L1 and αPD-L2 immunotherapy in aged versus young hosts includes T-cell stem cell effects and PD-L2 expression differences
Authors: Garcia Myrna G , Padron Alvaro S , Deng Yilun , Kancharla Aravind , Reyes Ryan M , Gupta Harshita B , Curiel Tyler J 
Published: January 2023

Abstract
Aging is the biggest risk factor for cancer, yet little is known about how it affects cancer immunotherapy. Melanoma response to αPD-1/αPD-L1 correlates with CD8+ TCF-1+ T cell stem cell (TCSC) generation. We tested αPD-1 (100 μg/mouse), αPD-L1 (100 μg/mouse) or αPD-L2 (200 μg/mouse) in aged (18–24 months) and young (3–8 months) mice challenged orthotopically with B16 melanoma (SQ) or ID8agg ovarian cancer (IP). Tumors and draining lymph nodes (TDLN) were analyzed by flow. We previously reported that αPD-1 treats young and aged with B16 and αPD-L1 only treats young. αPD-L2 treated B16 in aged but not young, the first single agent cancer immunotherapy exhibiting this property. Preliminary data indicate survival benefit of αPD-L2 against ID8agg in aged but not young mice. Aged mice tolerated all treatments comparable to young. B16 efficacy in young (αPD-1, αPD-L1) and aged (αPD-1, αPD-L2) correlated with increased TCSC and total TIL, but TCSC differed by age and treatment. PD-1 interacts with PD-L1 and PD-L2 while PD-L1 interacts with PD-1 and CD80. Aged mice expressed significantly more T-cell PD-1 and PD-L2 and up to 40-fold more PD-L2, PD-L1 and CD80 vs. young on myeloid cells and NK cells. We generated bone marrow-derived DC with GM-CSF. Aged DC expressed much high PD-L2 versus young, suggesting a cell-intrinsic PD-L2 age bias. Treatment differences in aged versus young could depend on these immune checkpoint or TCSC differences. We are now identifying mechanisms for increased PD-L2 and contributions to αPD-L2 efficacy in aged, and testing TCSC effects on treatments. Our work can improve cancer immunotherapy in aged hosts and provide models for treatment resistance in young hosts.
A phosphotyrosine switch controls antitumor activity of estrogen receptor b
Authors: Yuan Bin , Clark Curtis A , Yang Jing , Wu Bogang , Hu Yanfen , Curiel Tyler J , Li Rong 
Published: January 2023

Abstract
Recently, we identified a phosphotyrosine residue in human ERb (pY36), which is highly conserved in all mammalian ERb orthologs, but not present in ERa. In addition, this phosphotyrosine switch in ERb controls its tumor-intrinsic (tumor cells) activity. However, the weakness of the current literature concerns limited information about the ERb tumor-extrinsic antitumor activity. To investigate ERb tumor-extrinsic antitumor activity, we generated a whole-body knock-in (KI) mouse model in which the tyrosine residue Y55 of endogenous mouse ERb, which corresponds to Y36 of human ERb, is mutated to phenylalanine (Y55F). We found that B16 melanoma grew more robustly in KI recipient mice than in their WT counterparts, as well as MC38 and M-Wnt tumor models. These data demonstrate that the phosphotyrosine switch is important for ERb tumor-extrinsic antitumor activity in multiple tumor types and in both sexes of recipient mice. In the following mouse bone marrow chimera experiment, we found B16 melanoma growth was significantly faster in KI&gt;WT chimeras versus male WT&gt;WT control. This suggests that KI-derived immune cells poorly deterred tumor growth. Analysis with enriched subpopulations of immune cells from spleen, CD8 T cells have ERb protein expression. Adoptive transfer of CD8 T cells from WT donor but not KI donor significantly reduced tumor growth in Rag1 KO mice, a function attributed to reduced infiltration of KI CD8 T cells into tumors. Accordingly, increased infiltration of CD8 T cells was positively associated with ESR2 expression in various cancer types from TCGA datasets, including breast cancer and melanoma.
Adrenergic stress regulates the exhausted phenotype of T cells in the tumor microenvironment
Authors: Qiao Guanxi , Chen Minhui , Mohammadpour Hemn , Bucsek Mark , MacDonald Cameron , Hylander Bonnie , Repasky Elizabeth 
Published: January 2023

Abstract
We have shown previously that host adrenergic stress (model of standard ambient temperature-induced chronic stress) slows tumor progression by enhancing CD8+ T-cell activation and limiting the suppressive function of myeloid-derived suppressor cells in the tumor microenvironment (TME). We also found that reducing/blocking β-adrenergic receptor (β-AR) signaling significantly improves anti-tumor immune responses and efficacy of immune checkpoint immunotherapy. It has been reported that expression of immune checkpoint receptors (e.g. PD-1, TIM3, LAG3) is characteristic of exhausted T-cells and has been linked to failure of immune checkpoint inhibitors. Now we report that host adrenergic stress plays a previously unrecognized role in regulating T-cell exhaustion in the TME. In murine melanoma and colon cancer models, we found that propranolol (a pan β-AR blocker) significantly reduces the number of exhausted T-cells expressing immune checkpoint receptors in the TME and increases numbers of T-cells expressing effector cytokines. The overexpression of immune checkpoint receptors has also been associated with mitochondrial dysfunction. Our previous work shows that β-AR signaling during CD8+ T-cell activation in vitro impairs metabolic reprogramming. In new in vivo data, we observed that propranolol treatment increases both glycolysis and oxidative phosphorylation in tumor infiltrating CD8+ T-cells. Together these data suggest that β-AR signaling is a significant factor regulating the functional status of CD8+ T-cells in the TME. Blockade and/or reduction of adrenergic stress has the potential to improve anti-tumor immunity as well as the efficacy of immune checkpoint inhibitors.
Adjuvant combinations activate dendritic cells and contribute to antigen-specific CD4 T cell expansion
Authors: Bauer David Laurence , Kurtz Jonathan R , Grant Samuel B , Immethun Vicki E , McLachlan James B 
Published: January 2023

Abstract
Adjuvants are important mediators of immune responses and enhance the activation of innate immune cells, leading to protective T and B cell responses. Only a few vaccine adjuvants are currently approved for use in the US and, along with the discovery of novel adjuvants, combination adjuvants are likely to have a major impact on future vaccine development. Here, we investigated the ability of both the double mutant Escherichia coli heat labile toxin R192/L211A (dmLT) and the TLR4 agonist monophosphoryl lipid A (MPL-A) to drive innate and adaptative immune responses independently and in combination. We found that the combination adjuvant induces more robust activation of dendritic cells (DCs) than either adjuvant alone, leading to the formation of the NLRP3 inflammasome complex and increased secretion of IL-1β, as well as other hallmark pro-inflammatory cytokines. Furthermore, RNA sequencing and ingenuity pathway analysis support that the combination adjuvant may allow these DCs to polarize a multi-faceted Th1/2/17 CD4 T cell response. To determine how this adjuvant combination might regulate CD4 T cell responses, we intradermally immunized mice with a model T cell antigen in conjunction with dmLT or MPL-A alone or combined and, using MHC class II tetramers, found that vaccination with the combination demonstrated the greatest expansion and activation of endogenous, vaccine-specific CD4+ T cells in all lymphoid tissues assessed which included a Th1/Th17 response. These results reveal how combination adjuvants can be used to not only potentiate better vaccine responses, but to potentially bias the immune response to one that is more capable of combating infection.
Development of Nanogel-based Nasal Vaccine against Pneumonia
Authors: Nakahashi Rika , Yuki Yoshikazu , Fujihashi Kohtaro , Kiyono Hiroshi 
Published: January 2023

Abstract
Streptococcus pneumoniae (S. pneumoniae) cause pneumococcal disease in children and adults all over the world. Although there are vaccines comprising several pneumococcal polysaccharides in clinical use, they cannot cover the broad protections. Recently we established the cationic nanogel-based nasal vaccine against Pneumonia using a recombinant protein of pneumococcal surface protein A (PspA). We have designed three PspA chimeric antigens for trivalent vaccine and combined them with a cationic nanogel, a novel drug delivery system which adhere to the epithelial layer of the nasal cavity after nasal immunization and elicit the effective immunity by sustained antigen release. Indeed, the PspA nanogel vaccine induced not only the antigen-specific IgG in the body but also the antigen-specific secretory IgA (SIgA) at the mucosal surfaces such as nasal cavity where the entrance of pathogens. Both induced antigen-specific IgG and SIgA could bind to various serotypes of S. pneumoniae, indicating that these antibodies have neutralizing activity against broad types of S. pneumoniae. Moreover, the vaccinated mice were protected from infections by a several types of S. pneumoniae, and the nasal vaccine exhibited protective efficacy in some strains which cannot be covered by the current vaccines. Thus, our findings demonstrated the nasally administered PspA nanogel vaccine effectively elicit a protective immunity and provide a broad protection against S. pneumoniae infections.