bluuebunny/crossref_metadata_2025_split huggingface dataset:
The gut microbiota transfers the therapeutic effect of inhibiting glucose metabolism in lupus-prone mice
Authors: Elshikha Ahmed Samir , Brown Josephine , Kanda Nathalie , Ge Yong , Teng Xiangyu , Abboud Georges , Choi Seung-Chul , Terrell Morgan , Garrett Timothy J , Mohamadzadeh Mansour , Morel Laurence 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease in which autoantibodies induce tissue damage including the kidney. Gut microbial dysbiosis contributes to SLE pathogenesis. An abnormal metabolism is a characteristic feature of SLE in which the inflammatory functions of CD4+ T cells rely on glycolysis. We have shown that treatment with 2-deoxy-D-glucose (2DG), a glycolysis inhibitor, reduced the expansion of germinal centers and eliminated the production of autoantibodies, ameliorating disease in lupus-prone mice, including (NZB × NZW)F1 and (NZW x BXSB)F1. Here we show that the 2DG treatment also maintained gut bacterial diversity, reduced the changes in bacterial populations that occurred as disease developed in these mice, and that it altered the distribution of fecal metabolites. We investigated the effect of fecal microbiota transplantation (FMT) from 2DG-treated or control mice into pre-autoimmune lupus-prone mice of the same strain. In both strains, FMT from 2DG-treated mice was highly protective, with a reduction or elimination of anti-dsDNA IgG production, immune cell activation, and renal pathology compared to FMT from control mice. Overall, our results demonstrated for the first time that the therapeutic effect of glucose inhibition in lupus is transferable through the gut microbiota. This implicates either a direct effect of glucose on pathogenic gut bacteria, or an indirect effect through the immune system normalized by glucose inhibition.
Supported b R01 AI143313
Prevention of Type 1 Diabetes via a Lipid Nanoparticle-Based Oral Immunotherapy that Targets Selective Lymphoid Tissues
Authors: Raimondi Giorgio , Zhang Yichuan , Hou Shenda , Wang Jialu , Calderon-Colon Xiomara , Tiburzi Olivia , Lozano Marcos Igleasias , Patrone Julia 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is an untreatable autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Antigen presenting cells (APCs) malfunctions and aberrant accumulation of type 1 interferons contribute to T1D, and the inhibition of inflammatory cytokines signaling via JAK inhibitors like Tofacitinib (Tofa) has shown promise in the prevention of the disease. However, maintenance of a therapeutic concentration of these drugs is challenging and their prolonged use leads to significant side effects. Our objective was to design a controlled and localized delivery of Tofa via lipid nanoparticles (LNp) and assess the impact of an oral short-term administration strategy on T1D development.
We identified a LNp formulation with negligible toxicity, readily taken up by multiple immune cells, and with favorable Tofa encapsulation efficiency. Live animal imaging confirmed these particles have the unique property of accumulating in lymphoid tissues, particularly in pancreatic and mesenteric lymph nodes when administrated via oral gavage. Importantly, short-term administration (5 gavages once every other day) of Tofa-LNp early (3-week-old) or late (10-week-old) in disease prone NOD mice promoted a significant delay of T1D onset. Cell profiling and in vivo challenges indicated that this therapeutic effect is likely due to localized inhibition of APCs maturation and, surprisingly, promotion of anergy in diabetogenic T cells. Ex-vivo stimulation confirmed the hyporeactivity of these cells and adoptive transfer experiments confirmed their ability to act as reservoir of induced regulatory T cells. These results highlight the versatility of this novel LNp-based drug delivery strategy.
This work was supported by grant 2-SRA-2016-310-S-B from the Juvenile Diabetes Research Foundation.
IL-33 upregulated in fibroblastic reticular cells after recipient conditioning acts as a novel costimulatory signal in the generation of alloreactive Type 1 T helper cells
Authors: Dwyer Gaelen K , Mathews Lisa , Lucas Anna , Blazar Bruce R , Poholek Amanda , Shlomchik Warren , Turnquist Heth Roderick 
Published: January 2023

Abstract
In allogeneic hematopoietic stem cell transplantation (alloHCT), recipient conditioning releases Pathogen- and Damage-Associated Molecular Patterns (PAMPs and DAMPs) that generate pro-inflammatory antigen-presenting cells (APC) that secrete IL-12 to initiate donor Type 1 T helper (Th1) responses causing graft-vs-host-disease (GVHD). Yet, other mechanisms exist to initiate alloimmune responses, as recipients with disrupted APC PAMP/DAMP signaling or lacking IL-12 develop GVHD. We used IL-33 receptor, ST2, deficient B6 mice as T cell donors into BALB/c recipients to test the hypothesis that the DAMP IL-33 bypasses APC and acts directly on donor CD4+ T cells to mediate early alloreactive T cells activation and differentiation. In our model, we transferred equal ratios of B6 Cd4-Cre x St2fl/fl (ST2ko) and Cd4-Cre (ST2wt) T cells into irradiated BALB/c recipients with and without IL-12 blockade. Donor T cells in the secondary lymphoid organs (SLOs) were characterized at days 1–3, 5, and 7 post alloHCT. We established that IL-33 DAMP functions involve the direct stimulation of donor CD4+ T cells, which promoted IL-12-independent Type 1 T helper cell (Th1) differentiation and expansion. We demonstrated that IL-33 is induced by recipient irradiation in PDPN+ CD31− fibroblastic reticular cells (FRC) of the SLOs as early as 1 day post-radiation to increase alloreactive CD4+ T cell numbers. Mechanistically, IL-33 amplified CD4+ T cell TCR signaling in response to alloantigen to enhance Th1 cell activation and differentiation, while inhibiting regulatory molecule (i. e. IL-10 and Foxp3) expression. Thus, IL-33 is an unappreciated costimulatory signal in Th1 generation and a promising early target to prevent acute GVHD after alloHCT.
Supported by NIH F30AI147437 and T32 CA082084 (GKD), NIH R01HL122489, R01AR073527, R56AI13927 (HRT)
Deficiency of antibody-suppressor CXCR5+CD8+ T cells (not CD4+ Tregs) drives high alloantibody production in CCR5 KO kidney transplant recipients
Authors: Han Jing Light , Zimmerer Jason , Zeng Qiang , Chaudhari Sachi , Breuer Christopher , Bumgardner Ginny L 
Published: January 2023

Abstract
Kidney transplant (KTx) into CCR5 KO mice is an excellent model to study AMR immunobiology due to a heightened humoral response posited to be secondary to impaired CD4+ Treg cell trafficking to the allograft. We have observed that adoptive cell therapy (ACT) with alloprimed CXCR5+ CD8+ T cells mediates significant reduction of alloAb titer in CCR5 KO KTx recipients. We hypothesized that CXCR5+ CD8+ T cells are more potent inhibitors of alloAb production than CD4+ Tregs. We found that CCR5 KO recipients have significantly fewer CXCR5+ CD8+ T cells (782±183 vs 2058±167 cells/mm3) and graft-infiltrating CD4+ Treg cells (CD25+ FoxP3+; 12.9±8.8 vs 56.2±8.8 cells/mm3) compared to WT recipients, as well as significantly greater quantity of splenic germinal center (GC; GL7+ Fas+ B220+) B cells (5814±436 vs 671±342 cells/mm3; all p&lt;0.003). CCR5 KO recipient alloAb titer is significantly reduced following CXCR5+ CD8+ T cell ACT (1259±436 vs 5951±404 in untreated controls; p&lt;0.0001) but not following CD4+ Treg ACT (5688±436). CXCR5+ CD8+ T cells reduced splenic GC B cell (5813±589 to 4087±537; p=0.002) quantity, while CD4+ Treg had no impact (6916±538/mm3). Compared to untreated controls, CD8-depletion in WT recipients led to significant increase in alloAb titer (1508±338 vs 6078±436) and GC B cells (671±436 vs 7761±430; p&lt;0.0001 for both). CD4+ Treg depletion led to increased alloAb titer (3180±436) and GC B cell quantity (4911±429; p&lt;0.004 for both), though less pronounced than in the CD8-depleted group (both p&lt;0.001). This suggests that CXCR5+ CD8+ T cells are more potent regulators of alloAb production than CD4+ Tregs and their deficiency in CCR5 KO recipients is the major driver of heightened humoral immunity and AMR following KTx.
Supported by NIH R01 AI083456 (to GLB), T32 AI106704-07 and F32 AI161844 (to JLH), CA016058, UL1TR002733, the OSU Division of Transplant Surgery, and the OSU College of Medicine.
CMV drives phenotypic changes in CD4 T cells prior to but not during the first year after solid organ transplantation
Authors: Higdon Lauren E , Ahmad Ayah A , Maltzman Jonathan S 
Published: January 2023

Abstract
Cytomegalovirus (CMV) infection is a major complication after solid organ transplantation. The virus establishes latency after immune clearance of the primary infection. Immunosuppression impairs immune control in transplant recipients. We have previously shown that CMV drives accelerated immune aging of CD8 T cells in the first year after transplant. CMV-specific CD4 T cells also contribute to resolution of post-transplant viremia and reduce severity of disease at least in part by promoting maintenance of anti-viral CD8 T cell populations. Thus, we investigated the impact of CMV on CD4 T cell differentiation in the first year after transplant. Compared to CMV seronegative (CMV−) recipients, CMV+ recipients had an elevated frequency of aged (CD57+) CD4 T cells, with trends towards elevated PD-1+ and skewing toward memory rather than naïve phenotype. Unlike CMV-specific CD8 T cells, these phenotypes were stable over the first year after transplant, indicating these differences demonstrate a pre-established differentiation state. To correlate these findings to T cell receptor repertoire at a single cell level, we conducted single cell sequencing of TCR coupled to gene expression in CMV-responsive CD4 T cells from 6 transplant recipients from pre- to one-year post-transplant. Cell phenotypes were stable over time, and clonally expanded cells predominantly had an aged cytotoxic phenotype. Thus, CMV-responsive CD4 T cells in transplant recipients display evidence of immune aging and cytotoxicity. This is consistent with similar phenotypes in CD8 T cells, but striking in stability. Further study of this population will be important to determine whether this pre-existing phenotype is protective or pathogenic after transplant.
This work was supported by funding from the NIH to LEH (NIDDK 5K01DK123196) and AAA (Stanford PreRenal Initiative, NIDDK KUH 1R25DK122957) and the Department of Veterans Affairs to JSM (CSR&D 1I01CX001971).
Lipoxin A4 mitigates ferroptosis via FPR2 signaling during lung ischemia-reperfusion injury
Authors: Sharma Ashish Kumar , Cai Jun , Leroy Victoria , Tu Zhenxiao , Gonzalez Alejandro , Hartman Joseph , Mulligan Jennifer , Atkinson Carl , Upchurch Gilbert 
Published: January 2023

Abstract
Ischemia-reperfusion injury (IRI) after lung transplantation entails dysregulation of inflammation-resolution pathways leading to primary graft dysfunction. We investigated the role of ω-3-derived specialized pro-resolving lipid mediators, i.e. Lipoxin A4 (LxA4), and formyl peptide receptor (FPR2) signaling in the resolution of lung IRI. We used an established murine model of lung hilar ligation for IRI using C57BL/6 wild-type (WT) and FPR2−/− mice that underwent sham surgery or IRI (1hr left lung ischemia followed by 6- or 24hrs reperfusion). Lung function was measured using an isolated, buffer-perfused apparatus. Cytokine levels were measured in bronchoalveolar lavage (BAL) fluid, and neutrophil infiltration was assessed by immunohistochemistry. Post-lung transplant BAL from human patients was analyzed by liquid chromatography-mass spectrometry that demonstrated a significant increase in LxA4 on day 7 compared to days 0 and 1. In the murine model, we observed a significant increase in hallmarks of ferroptosis i.e. induction of lipid peroxidation (malonyldialdehyde), inhibition of glutathione peroxidase 4 (GPX4) as well as nuclear factor erythroid 2 (Nrf2) after IRI. Treatment of WT mice with recombinant LxA4 significantly attenuated lung dysfunction (decreased airway resistance and pulmonary artery pressure, and increased pulmonary compliance), inflammation (IL-17, TNF-a, CXCL1, HMGB1), injury (neutrophil infiltration) and ferroptosis (decreased MDA as well as increased Nrf2 and GPX4 expressions) compared to IRI alone, that was abolished in LxA4 treated-FPR2−/− mice. Collectively, our results indicate that lung IRI is regulated by ferroptosis which can be prevented by LxA4/FPR2-mediated signaling.
PP4 inhibition stimulates anti-tumor immunity in ovarian cancer
Authors: Curtis Marion R , Raja Remya , Wu Christopher , Rubino Thomas , Utagawa Emma , Magtibay Paul , Butler Kristina 
Published: January 2023

Abstract

Background
Increased infiltration of T cells into ovarian tumors has been repeatedly shown to be predictive of enhanced patient survival. However, despite the evidence of an active immune response in OC, immune checkpoint blockade therapy has been ineffective. Recently studies have shown that deficiencies in the DNA damage response (DDR) can drive increased genomic instability and tumor immunogenicity. One target involved in the DDR that has the potential to be of therapeutic value is protein phosphatase 4 (PP4); however, the effect of PP4 deficiency on anti-tumor immunity remain unknown.

Results
Our results show that PP4 inhibition combined with carboplatin leads to increased carboplatin sensitivity, DNA damage, and micronuclei formation. Using a panel of ovarian cancer cells, we show that PP4 inhibition triggers inflammatory signaling via NFκB and STAT1 activation resulting in increased expression of pro-inflammatory cytokines including IFNβ1, CCL5, CXCL10, and IL-6. We further show that PP4 inhibition and carboplatin-induced STAT1 activation is significantly blunted upon STING knockdown in ovarian cancer cells. Moreover, using mouse ID8 ovarian cancer cell line and OT-I cells, we demonstrate that the combination of PP4 inhibition and carboplatin significantly increased CD8 T cell migration over carboplatin treatment alone. In addition, the same treatment resulted in enhanced NK cell-mediated tumor cell killing and T cell killing in an autologous human organoid model.

Conclusions
Our work has identified a role for PP4 inhibition in promoting anti-tumor immune activation. These findings provide the rationale for combining PP4 inhibitors with immunotherapy as a new approach in ovarian cancer treatment.
Supported by DOD W81XWH2110489
Complement C3 deficiency enhances anti-CD47 efficacy in murine ovarian cancer model.
Authors: Suzuki Sora , Giridharan Thejaswini , Khan A N M Nazmul , Emmons Tiffany R , Yaffe Michael B , Weiskopf Kipp , Das Madhumita , Eng Kevin H , Zsiros Emese , Segal Brahm H 
Published: January 2023

Abstract
Epithelial ovarian cancer (OC) is the most lethal gynecological malignancy. While OC is an immunogenic tumor, single-agent anti-PD-1 have limited efficacy in recurrent OC. Blockade of the CD47/SIRPα pathway, a phagocytosis checkpoint in macrophages and other myeloid cells, can enhance myeloid-driven antitumor immunity and tumor control. However, the benefit of targeting CD47/SIRPα in recurrent OC has been limited. Prior work from our lab and others point to complement priming of innate immune responses as a barrier to T-cell-driven anti-tumor immunity. However, in the specific context of anti-CD47 therapy, complement opsonization of tumor cells could augment the capacity of myeloid cells to phagocytose or injure tumor cells. The role of complement deficiency with anti-CD47 therapy in tumor control is a gap in the field, we therefore evaluated the efficacy of anti-CD47 in female wild-type (WT) versus C3−/− and C5aR1−/− with syngeneic OC (ID8). Mice (n=8–10 per group) were administered IP ID8 tumor cells followed by anti-CD47 or isotype twice weekly for 3 weeks and were monitored for the ascites development and survival. On day 84, all WT mice treated with isotype had ascites by visual inspection and 3 of 10 died. The proportion of mice with ascites varied in other groups, C3−/− mice treated with anti-CD47 having the lowest proportion, 4 of 9 mice with ascites and no deaths (Fisher’s test, WT-isotype vs C3−/− + anti-CD47, p= 0.01). A limitation is the potential endogenous complement production by tumor cells, which will be evaluated. These results suggest a potential benefit for dual targeting of the CD47/SIRPα and complement pathways in OC. Additional studies will probe immunologic correlates and survival benefits of these therapies in OC.
This work was supported by Roswell Park Cancer Center Support Grant P30CA016056 and Apellis Pharmaceuticals, Inc
Malignant cell expression of the aryl hydrocarbon receptor induces PD-L1 and immunosuppression in models of oral and lung cancer
Authors: Snyder Megan , Kenison Jessica , Lara Brian , Wang Zhongyan , Pichardo Tachira , Yang Kangkang , Mazzilli Sarah , Sherr David 
Published: January 2023

Abstract
Immunotherapy has shown dramatic results in treating cancer but only in a minority of patients, so there is unmet need to understand the regulation of immune suppression in tumors. We have shown that the aryl hydrocarbon receptor (AhR) is a central player in regulating immune checkpoints in oral squamous cell carcinoma (OSCC) and may play a similar role in lung cancer. Orthotopic transplant of mouse AhR-knockout (KO) OSCC (MOC1) cells led to complete rejection of tumor formation coupled with increased T cell activation in tumor draining lymph nodes (tdLNs) and T cell signaling in tongues, whereas wild type (WT) OSCC challenge led to tumor formation and upregulation of T cell exhaustion pathways and checkpoint molecules. Similar patterns of AhR-facilitated immune protection appear in our lung cancer model. On average, mice transplanted subcutaneously with CMT167AhRKO lung adenocarcinoma cells survive up to twice as long as their WT-challenged counterparts; up to 50% of CMT167AhRKO-transplanted mice never grow tumor and also were partially protected from challenge with CMT167WT cells. CMT167WT-transplanted mice exhibited increased numbers of CD4+ and CD8+ in tdLNs and decreased T cell trafficking to tumors while the proportion of PD1+, CTLA4+ and Lag3+ CD4+ and CD8+ T cells were significantly lower in CMT167AhRKO tumors. AhRKO in both cell lines decreases PD-L1 expression by 50%, suggesting a mechanism of immune escape by WT tumors. Thus, the immunological protection following transplantation of both AhRKO CMT167 and MOC1 cells suggests downregulation of PD-L1 on malignant cells is at least partially responsible for immune enhancement in AhRKO cells and supports AhR’s potential as a viable immunotherapeutic target in at least two cancers.
Supported by grants from the NIH (R21 ES029624-01, R01 ES029136) as well as Find the Cause Breast Cancer Foundation and Johnson & Johnson Lung Cancer Initiative.
Immunological profiling of tumor-infiltrating CD8+ T lymphocytes in non-small cell lung cancer, head and neck squamous cell carcinoma, breast cancer, and renal cell cancer
Authors: Miller William L , Koguchi Yoshinobu , Kaufmann Johanna K , Yanamandra Niranjan , Griffin Sue , Smothers James , Redmond William L 
Published: January 2023

Abstract
To explore whether the variation in clinical response to immune checkpoint blockade (ICB) reflects intrinsic characteristics of tumor-infiltrating lymphocytes (TIL), TILs from multiple tumor types were analyzed by multiparameter flow cytometry. Recent work identified CD39+ CD103+ double positive (DP) CD8 TIL as tumor-reactive, therefore we assessed this phenotype in primary NSCLC (n=28), BCa (n=23), HNSCC (n=23), and RCC (n=23) specimens. TILs from NSCLC and HNSCC had significantly higher frequencies of DP T cells than BCa and RCC (NSCLC: median=34.2, IQR=15.0–53.8%; HNSCC: median=28.6%, IQR=13.5–44.5%), while TILs from BCa and RCC had low frequencies of DP T cells (BCa: median=2.4%, IQR=1.1–3.9%; RCC: median=4.2%, IQR=1.5–16.6%). Additionally, DP cells in NSCLC and HNSCC were co-expressed immune checkpoint markers PD-1, TIM-3, and LAG-3 at a higher frequency than RCC or BCa (P&lt;0.05). DP CD8 T cells in NSCLC and HNSCC also exhibited increased effector potential (granzyme B+) as compared to BCa and RCC, suggesting functional differences. Expression of the transcription factor Eomesodermin, associated with T cell exhaustion, was higher in effector CD8 T cells from RCC (median=84.5%, IQR=44.9–97.4%) as compared to NSCLC (median=28.7%, IQR=20.7–61.4%), BCa (median=30.1%, IQR=0–50%), and HNSCC (median=40.3%, IQR=20.1–61.2%). Additionally, 4-1BB, an indicator of TCR engagement, trended higher in RCC (mean=8.6%, IQR=1.4–46.7%) as compared to BCa (median=1.9%, IQR=0.4–8.6%). These data highlight the heterogeneity of human TILs isolated from distinct tumor types and provide insight into the basal expression of actionable therapeutic targets.
Supported by GlaxoSmithKline and the Providence Portland Medical Foundation
Identification of a subset of tumor-reactive CD8 TILs expressing NKG2A in HNSCC and CRC
Authors: Fesneau Olivier , Samson Kimberly , Rajamanickam Venkatesh , Ross David , Duhen Thomas 
Published: January 2023

Abstract
Even though blocking the interaction of NKG2A with its ligand HLA-E is a promising strategy to restore the function of cytotoxic T cells and induce tumor cell killing, several aspects of the biology of NKG2A+ CD8 T cells remain to be understood to fully benefit from this therapeutic approach. Here, we characterize the expression of NKG2A on tumor-infiltrating CD8 T cells (CD8 TILs) in patients with head and neck squamous cell carcinoma (HNSCC) and microsatellite-stable colorectal cancer (CRC). Our results show that NKG2A is primarily expressed by a population of tumor-reactive CD8 TILs identified by coexpression of CD39 and CD103 (DP CD8). NKG2A expression was stable and maintained during in vitro expansion. Interestingly, while TCR stimulation in presence of IL-15 and TGF-β are thought to be responsible for NKG2A upregulation, our in vitro results suggest that other factors might be necessary to induce its expression on naive CD8 T cells. Ex vivo analysis of NKG2A+ DP CD8 TILs by scRNAseq and flow cytometry revealed that those cells were activated, more differentiated, and displayed a cytolytic profile suggesting a role in tumor recognition and killing. Finally, we found that, even though there was a high degree of clonal overlap between NKG2A+ and NKG2A− DP CD8, some CDR3 TCR sequences were enriched in one versus the other subset. Consequently, HPV-reactive cells were preferentially enriched in NKG2A− DP CD8 TILs. Altogether, our results provide evidence that NKG2A is expressed by tumor-reactive CD8 TILs in HNSCC and CRC. However, NKG2A-inducing factor(s) remain to be identified and might provide new potential drug targets to bolster anti-tumor immune responses in cancer patients.
Supported by the Providence Portland Medical Foundation.