bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD103+ cDC1 vaccine efficacy in murine breast cancer is inhibited by STAT3
Authors: Chrisikos Taylor T , Zhou Yifan , Li Haiyan S , Babcock Rachel Lauren , Wan Xianxiu , Patel Bhakti , Newton Kathryn , Mancuso James , Watowich Stephanie S 
Published: January 2023

Abstract
Conventional dendritic cells (cDCs) are a crucial immune population, which includes multiple subtypes that coordinate adaptive immunity and tolerance. Migratory type 1 cDC1s (CD103+ cDC1s in mice) are required to induce CD8+ T cell-mediated anti-tumor immunity, yet whether and how tumors regulate CD103+ cDC1 function is largely unknown. Many tumor-associated immunosuppressive cytokines, such as interleukin (IL)-10, require Signal Transducer and Activator of Transcription 3 (STAT3) for intracellular signaling; therefore, we sought to determine whether STAT3 inhibits CD103+ cDC1-mediated anti-tumor immunity. Indeed, we found that in vitro-derived STAT3-deficient (Stat3Δ/Δ) CD103+ cDC1sare resistant to IL-10 – mediated inhibition of Toll-like receptor 3 (TLR3)-agonist induced maturation. When used as an anti-tumor vaccine, Stat3Δ/Δ CD103+ cDC1s inhibited breast tumor growth and increased mouse survival to a greater degree than STAT3-sufficient CD103+ cDC1s. Vaccination with Stat3Δ/Δ CD103+ cDC1s increased tumor antigen-specific CD8+ T cells and IFN-g+ CD4+ T cells in tumors and tumor-draining lymph nodes compared to controls. Moreover, IL-10 receptor-deficient CD103+ cDC1s restrained tumor growth as effectively as Stat3Δ/Δ CD103+ cDC1s. Taken together, our results demonstrate STAT3 suppresses CD103+ cDC1 maturation and vaccine efficacy in breast cancer. The data also suggest IL-10 is an important factor in the murine mammary tumor environment mediating immunosuppressive STAT3 signaling in CD103+ cDC1s. Thus, STAT3 inhibition may provide an effective strategy for improving the anti-tumor efficacy of CD103+ cDC1-based vaccines.
Characterization of T cell responses induced following checkpoint inhibition therapy across multiple malignancies with a high tumor mutational burden
Authors: Moss Keith 
Published: January 2023

Abstract
Cancer vaccination has been idealized for the past two decades but has suffered from the lack of relevant and specific target antigens. Neoantigens, harboring neoepitopes, represent patient-specific mutated antigens which could potentially serve as immunotherapeutic targets. In the recent years, it has been observed that patients with a higher tumor-mutational burden (TMB) have better clinical responses to checkpoint inhibition therapy. TMB may become a potential criterion for the inclusion of patients in such immunotherapeutic trials. However, this observed correlation between TMB and improved clinical response has yet to be fully substantiated, especially in a pan-cancer setting.
This work presents preliminary data from a basket trial that has been undergoing at Rigshospitalet, Denmark. This trial contains patients presenting malignant tumors with a high TMB across multiple cancer types, those of which are undergoing various immunotherapies. Preliminary data indicates that neoepitope-specific CD8+ T cells can be detected in patient-derived tumor-infiltrating lymphocytes and PBMCs with the use DNA barcode labeled peptide-MHC (pMHC) multimers. Through FACS and NGS sequencing, immunogenic neopeptides may be identified from a library of personalized in silico predicted peptides. Thus, providing further support to the notion that high-throughput methods of antigen-specific T cell detection may be utilized to interrogate the contribution of TMB to clinical outcome in checkpoint inhibition therapy.
Agonistic anti-ICOS antibodies promote unexpected elimination of tumor infiltrating effector T cells in a FcγR-independent manner
Authors: Demane Dafne Sofia Franz , Joshi Kroopa , Costoya Cristóbal , Zervas Dimitrios , Solomon Isabelle , Peggs Karl S. , Quezada Sergio A. 
Published: January 2023

Abstract
Inducible T cell co-stimulator (ICOS) is a co-stimulatory receptor expressed on tumor infiltrating regulatory and effector T cells. ICOS potential role in cancer control is supported by the correlation between ipilimumab’s efficacy and the presence of CD4+ICOShi T cells in PBMC, as well as loss of tumor control in ICOS−/− and ICOSL−/− mice treated with anti CTLA-4.
37A10 is an anti ICOS agonistic mAb reactive to mouse and human ICOS, with a human IgG1 Fc region to promote depletion of regulatory T cells through antibody-dependent cellular cytotoxicity. We hypothesized a pure agonistic, non-depleting anti ICOS would promote co-stimulatory signals on activated T cells while avoiding depletion of activated ICOS+ T cells. Hence, we aimed to compare the efficacy in tumor control of two isotypes of 37A10. Both mIgG1 (non-depleting) and mIgG2a (depleting) isotypes failed to promote survival, as a monotherapy or in combination with anti PD-1 or anti CTLA-4. This was consistent with both isotypes promoting the elimination of activated T cells in an Fc-independent manner. Ablation of activated effector T cells with anti ICOS replicated loss of activated effector T cells upon in vivo blockade of ICOSL reflecting their ligand blocking activity. Moreover, both isotypes impaired the activity of anti CTLA-4, associated to effector T cell depletion, raising concerns regarding the use of anti ICOS mAbs as combination substrates in tumor immunotherapy.
The data suggest that agonistic antibodies that block the natural ligand binding site and have weak in vivo agonism could result in unwanted negative responses in cancer. Future work should aim to identify antibodies with robust agonistic activity in vivo while allowing signaling induced by the natural ligand.
Amplifying an abscopal effect of radiation therapy with a novel immunotherapeutic agent
Authors: Paez Patrick A , Liu Wenjie , Guo Chunqing , Mikkelsen Ross , Wang Xiang-Yang Shawn 
Published: January 2023

Abstract
Radiation therapy (RT) is one of the primary treatment modalities for head and neck squamous cell carcinoma (HNSCC). At the time of diagnosis two-thirds of HNSCC patients have local-advanced disease and 50–60% of these patients will experience a local-regional or metastatic relapse within three years. Improving the immunogenic response of RT may help address this clinical problem. However, current RT regiments have failed to reliably generate robust antitumor immunity as evidenced by the rarity of clinical abscopal responses. Recently we engineered a chimeric fusion molecule called Flagrp170, a novel immunostimulatory agent highly capable of promoting antigen presentation and T-cell activation. We hypothesize that the combination of RT and Flagrp170 provides superior immunogenic signals producing effective and durable antitumor immunity against HNSCC. We report that administration of Flagrp170 to the tumor sites upon RT using a small animal radiation research platform (SARPP) results in potent activation of antigen-presenting cells, increased functionality of tumor-infiltrating T-cells, and systemic immune augmentation, when compared to either monotherapy. Additionally, the combination treatment is able to reduce the dose of RT required for tumor control and protects previously cured animals from subsequent tumor re-challenge. Finally, the combination treatment can successfully control the contralateral untreated tumors, supporting the superior activity of Flagrp170 in potentiating abscopal responses of RT. Our data suggest that the Flagrp170 may be used to enhance immunogenic cancer cell death in RT and resultant protective antitumor immunity can potentially help reduce post-RT recurrence of HNSCC.
A trifunctional bispecific antibody mediates efficient killing of B-cell lymphoma cells
Authors: Cheng Ying , Sun Rui , Tian Zhigang 
Published: January 2023

Abstract
Natural killer (NK) cells are a type of cytotoxic lymphocytes critical to immune surveillance. The mechanisms for NK-mediated tumor elimination including natural cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC), and the secretion of interferon-γ (IFN-γ), which are essential for mediating the anti-tumor activity. CD19, a B-cell lineage-specific marker, is highly expressed in B-cell malignancies and an attractive target for therapy. Here, we generate a trifunctional bispecific antibody (TBAb) containing single chain antibody fragment (scFV) against CD16 and CD19 to create an immunologic synapse between NK cells and CD19+ lymphoma cells. X has been engineered with a modified human interleukin crosslinker for improving therapeutic efficacy. Specificity has been confirmed by investigating the ability of X to bind CD19+ tumor targets and CD16+ NK cells. We found that X TBAb mediated killing of human lymphoma B cell lines, including namalwa, daudi and raji, by human NK cells purified by microbeads or NK-cell amplification kit in vitro. X-mediated killing is accompanied by NK-cell activation, cytokine release and upregulation of TNF-related apoptosis-inducing ligand (TRAIL). Further, X TBAb demonstrated antitumor activity against lymphoma xenografts reconstituted with human PBMCs. These data provide a therapeutic candidate for the treatment of B-cell malignancies.
A new checkpoint receptor targets for cancer immunotherapy
Authors: Li yangyang , Tian Zhigang , Sun Rui 
Published: January 2023

Abstract
While blockade of the CTLA4 and PD1 pathways has emerged as an effective treatment of cancer, the majority of patients do not derive long term benefit. This has catalyzed enormous interest in the targeting of other immune checkpoint receptors. X protein is recently identified as a novel immune checkpoint receptor on human T cells. However, the function of murine X remains elusive. To investigate the role of murine X on immune cells, we generated anti-X antibodies and identified 11D7 with the ability to binding X and blocking X ligand binding. We found that X was not expressed on resting immune cells while it was upregulated upon cell activation. The expression of X was significantly upregulated on NK cells and CTLs in the tumor microenvironment. Furthermore, blockade of X with monoclonal antibodies inhibits tumor growth and prolong the survival of tumor-bearing mice. These data indicated that targeting X is a promising anti-cancer therapeutic strategy.
Reprogramming T Cell Specificity to Suppress Autoreactive T Cells in Type 1 Diabetes
Authors: Joglekar Alok V , Rankin Kobie , Ford Kelsey , Hicks Louise Teresa 
Published: January 2023

Abstract
Effector T cells (Teff) in Type 1 Diabetes (T1D) recognize antigenic targets on pancreatic β cells, thereby killing them. Insulin-derived epitopes are targeted first, followed by rapid epitope spreading, leading to progressive destruction of pancreatic islets, causing insulitis and T1D. Curbing these autoimmune responses is key to the development of immunotherapies to treat T1D. In this study, we tested the proof-of-concept of two strategies to treat T1D by reprogramming T cell specificity. We have developed cell-surface receptors called SABRs (Signaling and Antigen-presenting Bifunctional Receptors), which present a peptide-MHC complex on the extracellular domain and link it with a CD28-CD3ζ signaling domain. The intracellular signaling domains in SABRs are capable of activating T cell function. The extracellular domains can recognize TCRs specifically. We successfully demonstrated that SABRs presenting peptide epitopes on human and mouse, class I and class II MHC complexes are able to induce a functional signal through the NFAT pathway. We tested two complementary approaches to use SABRs to engineer T cells. In the first approach, we transduced human Treg cells with SABRs. SABR-armed Treg cells were able to secrete IL-10 in response to T cells bearing a diabetogenic TCR. In the second approach, we transduced human CD8+ T cells with SABRs. SABR-modified CD8+ T cells were able to specifically lyse target cells bearing a diabetogenic TCR. Ongoing studies will determine if Treg-mediated suppression or CD8+ T cell-mediated elimination of diabetogenic Teff cells will be an efficient strategy for immunotherapy for T1D. If successful, these approaches will also be applicable to other autoimmune diseases such as Multiple Sclerosis.
Optimization of CAR T cell co-stimulation reduces to MDSC suppression
Authors: Boucher Justin C , Cervantes Estelle V , Lee Sae Bom , Spitler Kristen , Reid Kayla , Davila Marco L 
Published: January 2023

Abstract
A major obstacle for continued development of CARs is their suppression by the tumor microenvironment. Clinical data from our lab shows patients that have increased myeloid cells have poorer outcomes to CAR T cell therapy. Based on this we examined MDSC suppression of CARs.
First, we examined the effect of MDSCs on CAR T cell production. We found gene transfer was lower for m1928z CAR T cells co-cultured with MDSCs compared to those that were not (24.1% vs 39.1%). There was also a reduction in total T cell counts for m1928z after MDSC co-culture (88%). We also investigated the effect of MDSCs on CAR T cells when present during antigen stimulation. Co-culture with MDSCs in vitro showed significant reductions in CAR T cell mediated killing and IFNγ secretion. Additionally, CAR T cells stimulated in the presence of MDSCs had lower expression of activation markers PD1 and LAG3. This suggests that MDSCs reduce CAR T cell gene transfer, activation, killing, and cytokine production.
To evaluate if we could create a CAR T cell resistant to MDSC suppression null mutations of YMNM and PRRP were incorporated into a CD28 CAR leaving only PYAP active (mut06). When mut06 and MDSCs were co-cultured there was a reduction in gene transfer (21% vs 38%) and T cell counts (80% vs 88%) compared to m1928z. We also found when in the presence of MDSCs mut06 was significantly better at killing compared to m1928z. To examine this in vivo we co-injected mice with CAR T cells and MDSCs. We found mice given m1928z with MDSCs had reduced CAR T cell function while mut06 was not affected by MDSCs. Overall our data shows that MDSCs can suppress CAR T cell function when present during production as well as CAR stimulation and optimizing CD28 CAR signaling creates CAR T cells that are more resistant to MDSCs.
CD4 depletion potentiates anti-tumor immunity in adoptive immunotherapy by increasing IL-18Rαhi endogenous CD8+ T cells
Authors: Kim Seon-Hee , Han Chungyong , Kwon Byoung S. , Choi Beom K. 
Published: January 2023

Abstract
Adoptive T cell therapy (ACT) requires lympho-depletion pre-conditioning to eliminate immune-suppressive elements to allow for the efficient engraftment of adoptively transferred tumor-reactive T cells. Because anti-CD4 monoclonal antibody depletes CD4+ immune-suppressive cells to enhance anti-tumor immunity, combinations of anti-CD4 treatment and ACT have synergistic potential in cancer therapy. We designed a post-ACT conditioning regimen that involves weekly treatment with anti-CD4 (CD4post). Using murine melanoma, cyclophosphamide and tumor-reactive CD8+ T cell infusion were included to represent an ACT model. We evaluated anti-tumor effects and immunologic changes of T cells. CD4post in ACT markedly increased tumor suppression and survival. Remarkably, CD4post worked differently on ex vivo primed CD8+ T cells versus endogenous CD8+ T cells. CD4post substantially increased the proliferation of ex vivo primed CD8+ T cells, while increasing endogenous CD8+ T cell differentiation and effector function. Endogenous CD8+ T cells upregulated activation/exhaustion markers and exhibited a skewed TCR repertoire, implying that CD4post boosted tumor-reactivity. Accordingly, CD4post-experienced endogenous CD8+ T cells showed enhanced intra-tumoral infiltration and exhibited greater anti-tumor activity against melanoma in vitro. Importantly, enrichment of the IL-18Rαhi subset was critical for boosting anti-tumor responses, as IL-18Rα+ cell-depletion CD8+ T cells resulted in diminished anti-tumor activity. This study highlights the clinical relevance of CD4post to ACT and gives insights into the characteristics of the immunological components that drive the augmented cancer–immunity cycle in ACT.
Activation of the hypoxia-inducible factor 1 alpha is necessary for type 1 interferon and IFN stimulatory gene expression during gammaherpesvirus infection
Authors: López D M , Mesri Enrique , Andreanksy Samita 
Published: January 2023

Abstract
Oxygen availability and the hypoxia-inducible factor 1 pathway (HIF1) influence the activity of cells involved in immune responses. Initially described as a master regulator of cellular adaptation to low oxygen concentration, activation of the hypoxia-inducible factor 1 alpha (HIF1α) is now recognized as an integral part of inflammatory cytokines production, phagocytic activity and bacterial killing by myeloid-derived cells. The goal of our studies is to determine the role of HIF1α during antiviral responses. We measure type 1 interferon gene expression in mouse embryonic fibroblasts lacking HIF1α activity (HIF1α Null MEFs) during early infection against the DNA virus, murine gammaherpesvirus 68 (MHV68). We recently reported that MHV68 activates HIF1atranscription activity and this is necessary for viral replication. In this study, analysis of mRNA levels by real-time qPCR, revealed that IFNβ1 decreased by 5-fold in HIF1α Null MEFs following 8 hours post infection (hpi), relative to wild-type, whereas levels of IFNα4, IFNα6 remained unchanged. Consistently, transcript levels of the IFN-stimulated gene OAS1β were reduced 7-fold relative to HIF1α WT MEFs. However, at 24hpi absence of HIF1α diminished expression of IFNα4, IFNα6, IFNβ1, OAS1β, IFIT18 and ISG20. In conclusion, these results suggest that HIF1α activity plays an important role during antiviral responses against dsDNA viruses.
Interferon gamma promotes long term retention of tissue resident memory T cells in the brain following alphavirus clearance in mice
Authors: Baxter Victoria Kate , Schultz Kimberly L.W. , Griffin Diane E 
Published: January 2023

Abstract
The prototypic alphavirus Sindbis virus (SINV) targets neurons in mice, providing a well characterized model of alphavirus encephalomyelitis. SINV clearance from the brain requires a noncytolytic mechanism to avoid neurological damage and dysfunction and is facilitated by synergistic cooperation between anti-SINV antibody and interferon gamma (IFN-γ). While infectious virus is cleared from the brain by 7 to 10 days post infection (DPI), SINV RNA levels decrease slowly and remain detectable at low levels for at least a year following infection. Because alphaviral RNA is infectious, strict control by the immune system is required to prevent virus reactivation and relapse of disease. To characterize the long-term T cell response following clearance of infectious virus, C57BL/6 mice with intact or impaired IFN-γ signaling were infected with the nonfatal TE strain of SINV, and the frequency and functionality of different T cell populations were evaluated in the brain by flow cytometry. While highly proliferative short-lived T effector cells made up the majority of CD4+ and CD8+ T cells during active infection at 7 DPI, long-lived effector memory T cells became the predominant T cell type by 14 DPI. Following the period of virus clearance, both CD4+ and CD8+ T cell polyfunctionality increased, with more cells expressing multiple effector proteins at higher intensities, and PD-1 and TIM-3 exhaustion marker expression decreased. The percentage of CD8+ T cells characterized as CD103+ tissue resident memory (TRM) cells was decreased in mice with impaired IFN-γ signaling. This indicates IFN-γ signaling promotes the development of TRM cells in the brain during SINV infection and suggests IFN-γ supports long term control of SINV reactivation.
Maternal interferon lambda signaling limits transplacental transmission and mediates fetal pathology during congenital Zika virus infection in mice
Authors: Casazza Rebecca L , Lazear Helen M 
Published: January 2023

Abstract
Zika virus (ZIKV) is among the few pathogens that can surmount the physical and immune barriers of the maternal-fetal interface to cause congenital infections. Immunity at the maternal-fetal interface is carefully balanced to protect the developing fetus from maternal immune rejection as well as maternal pathogens, and includes cytokines secreted by the placenta. Interferon lambda (IFN-λ) is secreted constitutively from human placental trophoblasts, and limits ZIKV transplacental transmission in mouse congenital infection models. To determine if IFN-λ is secreted from mouse placentas, we evaluated IFN-λ activity from placentas of mid-gestation and laboring dams. IFN-λ activity was present in infected and laboring placentas, but not in uninfected mid-gestation placentas, suggesting that IFN-λ is not constitutively secreted from mouse placentas. To define the tissues that respond to IFN-λ at the maternal-fetal interface, we assessed ZIKV transplacental transmission in mouse pregnancies in which either fetal or maternal tissues lacked the IFN-λ receptor (Ifnlr1−/−). Unexpectedly, the antiviral effects of IFN-λ resulted exclusively from signaling in maternal tissues, as fetal viral loads depended only on maternal Ifnlr1 genotype, not the fetal/placental genotype. Using mice also lacking the type I IFN receptor, we studied the effect of IFN-λ signaling in pregnancies with enhanced ZIKV replication and again found an antiviral effect of maternal IFN-λ signaling. Pregnancies with maternal IFN-λ signaling also exhibited enhanced fetal pathology, suggesting that IFN-λ signaling can contribute to fetal pathology in high-viremia models.
Differential of I-A
b
Immunopeptidome of Thymus, Splenic B cells, and Splenic DCs from C57BL/6 mice
Authors: Nanaware Padma Pandurang , Lu Liying , Stern Lawrence J. 
Published: January 2023

Abstract
Antigen presentation in the thymus is central to selection of CD4 and CD8 T cells. Despite postulated roles for differential central and peripheral antigen presentation pathways, comprehensive immunopeptidome analysis of the thymus has not been reported for either MHC I or MHC II. To map the immunopeptidome in the thymus of C57BL/6 mice presented by IAb, we used immunoaffinity coupled to mass spectrometry. We identified &gt;1000 peptides using data dependent acquisition strategy. One challenge in thymic peptidome analysis is the possibility of co-eluting non-specifically bound peptides present as a result of the low abundance of MHC II antigen presenting cells (&lt;10% of total thymic cells). We used several approaches to reduce non-specific background peptides, including analyzing elutions from isotype control antibody conjugated beads, considering only peptides present in nested sets and using predicted binding motif analysis to identify core epitopes. We compared the immunopeptidome of thymus to those of the more easily characterized splenic B cells and splenic DCs. Some of the core epitopes were unique to thymus, splenic B cells or splenic DCs, although most were shared. We observed a broader length distribution of thymic peptidome as compared to splenic B cell and DC peptidomes. To help understand these differences, we selected for detailed analysis 57 peptides representative of thymic derived, splenic B derived or shared peptidomes and studied their binding affinity to IAb. The results suggested that the pool of peptides presented by IAb in thymus has lower MHC affinity than does the pool presented by splenic B cells. Thus our data support the idea of differential antigen processing and presentation in central versus peripheral tissues.