bluuebunny/crossref_metadata_2025_split huggingface dataset:
TGFβ superfamily members regulate radiation-induced anti-tumor immunity.
Authors: Vanpouille-Box Claire I , Formenti Silvia C , Demaria Sandra 
Published: January 2023

Abstract
Transforming Growth Factor-beta (TGFβ) and activin A (actA) are TGFβ superfamily members with overlapping functions in many processes including regulation of inflammation and immunity. We have recently found that actA release by breast cancer cells is enhanced by radiotherapy (RT). Interestingly, prolonged exposure to TGFβ inhibitors also resulted in actA upregulation, consistent with a previously described compensatory mechanism. Here we hypothesized that actA and TGFβ regulate RT-induced anti-tumor immunity.
4T1 mouse breast cancer cell derivatives with inducible actA knockdown (KD) (4T1shActA) or non-silencing control (4T1shNS) were injected s.c. in mice (day 0). ActA KD was induced by doxycycline at day 8. TGFβ neutralizing antibody (1D11) was given i.p. every other day starting on day 12. 6Gy RT was delivered to the tumor on days 13, 14, 15, 16 and 17.
TGFβ blockade improved RT-mediated tumor control, an effect mediated by T cells. However, tumor recurred. Notably, ActA KD or 1D11 increased intratumoral Tregs (Control: 11%; 1D11: 26%, shActA: 21%) and enhanced Tregs infiltration induced by RT (RT: 15%; RT+1D11: 27%; RT+shActA: 30%). When both TGFβ and actA were blocked, Tregs significantly decreased in both untreated (1D11+shActA: 13%) and RT-treated tumors (RT+1D11+shActA: 8%). Tumor-specific IFNγ production by CD8+ T cells was higher in RT+1D11+shActA compared to RT+1D11 (*p) and RT+shActA (**p). ActA KD in mice treated with RT+1D11 reduced tumor recurrence and improved survival (RT+1D11 vs RT+1D11+shActA **p; RT+shActA vs RT+1D11+shActA ***p).
Data indicate that both TGFβ and actA impair RT-induced anti-tumor immune responses. Concomitant inhibition of actA and TGFβ is required for optimal in situ vaccination by RT.
Adjuvant Immunotherapy with Surgery Improves Survival in Murine Models of Thoracic Malignancies
Authors: Dunbar Ashley , Baldassari Michael , Connolly Courtney , Mizelle Jack , Newton Andrew , Singhal Sunil , Predina Jarrod 
Published: January 2023

Abstract

Objectives
Immunotherapy is an alternative therapy for thoracic malignancies, but results in humans have not been as impressive as anticipated. We hypothesized that adjuvant immunotherapy with surgery debulking can improve efficacy and long term response rates.

Methods
We retrospectively reviewed our group’s experience with human immunotherapy trials for NSCLC and mesothelioma. We developed murine models of NSCLC and mesothelioma surgery to evaluate clinically applicable immunotherapy approaches (tumor vaccination and checkpoint inhibitors) and optimized regimen. Outcomes were assessed for overall survival and tumor progression. Flow Cytometry, ELISA, PCR and in vivo neutralization assays were utilized to determine immune responses.

Results
The most important predictor of immunotherapy response in human trials was minimal disease at the time of immunotherapy. Surgery generates a state of minimum disease, thus we used a murine cancer surgery model to evaluate clinically available adjuvant immunotherapy approaches in a controlled setting. Adjuvant vaccination strategies were associated with decreased tumor volumes (p&lt;0.01) and were associated with an increase in postoperative survival (42 days vs 24 days, p=0.03). In vivo lymphocyte assays demonstrated only partial cytotoxic activity of CD8+ T-cells postoperatively. The addition of checkpoint inhibitor (CTLA4i) with tumor vaccination improved potency and nearly tripled post-operative survival (54 days vs 19 days; p=0.004). Additionally, 34% of mice receiving combination immunotherapy with surgery were cured (p=0.03).

Conclusion
This evidence supports a new approach to thoracic malignancies including multi modal immunotherapy with surgical resection.
Chemotherapy-induced tumor dormancy and relapse
Authors: Aqbi Hussein F , Butler Savannah E. , Keim Rebecca , Idowu Michael O. , Manjili Masoud H 
Published: January 2023

Abstract
Breast cancer mortality is due to distant recurrence of the disease as a result of awakening dormant tumor cells that were established by cancer therapies. The mechanisms through which dormant tumor cells are maintained or escape from dormancy, and relapse remain elusive. One such mechanism that may play a role in tumor dormancy maintenance or escape is autophagy; a process important in all cells for the removal of damaged proteins and organelles. Although autophagy is a mechanism of tumor suppression, it also confers stress tolerance that enables tumor cells to survive under adverse conditions. Here, we wanted to determine the role of autophagy in tumor dormancy and sensitivity of dormant tumor cells to immunotherapy, i.e., IFN-gamma treatment. A mouse mammary carcinoma (MMC) cell line was established from the neu over-expressing FVBN202 transgenic mouse. We also used Adriamycin (ADR) for the establishment of chemotherapy-induced tumor dormancy, and blocked autophagy by chloroquine (CQ). We demonstrated that a transient blockade of autophagy by CQ during ADR treatment prolonged tumor dormancy, in vitro, but not in vivo. Also, we determined that dormant tumor cells established by ADR or ADR+CQ were more sensitive to IFN-gamma induced apoptosis compared with non-dormant, proliferating tumor cells. These observations suggest that autophagy could participate, in part, in tumor dormancy without affecting the sensitivity of dormant cells to IFN-gamma treatment.
Combination therapy of a PI3K p110α-isoform-selective inhibitor and anti-HER2/neu antibody enhances the anti-tumor immunity in breast cancer mouse model
Authors: Choi Jae Hyeog , Kim Ki Hyang , Roh Kug Hwan , Jung Hana , Seo Su Kil , Choi Il Whan , Yea Sung Su , Park SaeGwang 
Published: January 2023

Abstract
Trastuzumab (Herceptin) is a humanized recombinant monoclonal antibody against HER2 that has shown the clinical benefit in HER2+ breast cancer patients. Because non-responders to trastuzumab have been observed, one strategy to overcome the resistance is combination therapy. Combination therapies with phosphoinositide 3-kinase (PI3K) inhibitors and trastuzumab (anti-HER2/neu antibody) are effective against HER2+ breast cancer mouse model. The therapeutic effect and anti-tumor immunity of combination therapy with an anti-HER2/neu antibody and a pan-PI3K inhibitor (GDC-0941) or a p110a isoform-selective inhibitor (A66) was evaluated in vivo breast cancer models. Combined the anti-neu and PI3Ki treatment synergistically occurred in anti-tumor immunity and HER2/neu-mediated memory T cell responses. In the presence of the anti-neu antibody, A66 was more effective in increasing the T cells and IFN-γ+ CD8+ T cells in TILs. IFN-γ ELISPOT data showed that tumor-specific T cells against neu and non-neu tumor antigens increased synergistically after combination PI3Ki and anti-neu treatment, and A66 was more potent. In a TUBO (neu+) and TUBO-P2J (neu-) mixed model representing IHC2+ tumors, A66 showed greater tumor mass control and survival prolongation than GDC-0941, when combined with the anti-neu antibody. Combined with the anti-neu antibody, A66 was more effective than GDC-0941, and A66 synergized with the anti-neu antibody in terms of anti-tumor immunity. We propose A66 plus anti-HER2/neu antibody as an effective strategy in trastuzumab-resistant breast cancers.
TLR-stimulated T cells acquire resistance to MDSC mediated suppression
Authors: Joseph Ann Mary , Parker Dominique , Hawkins Tarik , Ciavattone Nicholas , Davila Eduardo 
Published: January 2023

Abstract
The immunosuppressive tumor microenvironment presents a significant challenge to developing effective T cell-based cancer immunotherapies. Myeloid-derived suppressor cells (MDSCs), a heterogeneous group of cells, are a major contributor to the suppressive tumor microenvironment. MDSCs are immature myeloid cells that develop in response to chronic inflammation generated by an infection or a tumor. Currently, strategies to block MDSC-mediated suppression generate modest anti-tumor responses. This is in part due to lack of specific markers to target MDSCs and inability to simultaneously inhibit the multitude of suppressive mechanisms employed by MDSCs. Generating tumor-reactive T cells with the capacity to resist MDSC-mediated suppression would help facilitate the production of potent anti-tumor T cell therapies. The activation of the Toll-like receptor-Myeloid differentiation factor 88 (TLR-MyD88) signaling pathway in CD8+ T cells enhances cell proliferation, cytotoxic function, and survival. Our studies show that TLR-stimulated T cells are resistant to MDSC-mediated suppression. MyD88-activated CD8+ T cells co-cultured with tumor-derived MDSCs displayed enhanced proliferation and cytokine production over control T cells. Our future objectives are to understand the molecular mechanisms by which TLR-activated T cells acquire resistance properties and to exploit this knowledge to improve antitumor immune responses by overcoming MDSC-mediated suppression.
Targeting Sphingosine kinase 2/S1P axis Decreases Immunosuppressive Potential of Myeloid Derived Suppressor Cells (MDSCs) and Improves Tumor Control
Authors: Chatterjee Shilpak , Chakraborty Paramita , Paneerselvam Shanmugham , Ogretmen Besim , Mehrotra Shikhar 
Published: January 2023

Abstract
One of the major hindrances for harnessing therapeutic potential of T cells against tumor is the presence of immunosuppressive cells (MDSC, TAMs etc.) in the tumor microenvironment. Thus, strategies to boost the anti-tumor T cell function in vivo by overcoming immunosuppression holds merit. In the present study, we observed that MDSCs isolated from the tumor site have high expression of both Sphingosine kinase 1 (SphK1) and 2 (SphK2). However, genetic ablation of SphK2, but not SphK1, completely diminished the suppressive potential of MDSCs as evident by the increased proliferation and IFN-γ secretion by T cells co-cultured with SphK2−/− MDSCs. Similar dysfunctionality in suppressive potential was observed when MDSCs from ABC294640 (SphK2 specific inhibitor) treated tumor bearing mice was compared with vehicle control treated mice. The functional impairment of SphK2−/− MDSCs also contributed to the better tumor control when melanoma epitope gp100 reactive CD8+ T cells were adoptively transferred to treat subcutaneously established B16 melanoma tumor bearing SphK2−/− mice, as compared to those transferred in WT tumor bearing host. Studies delineating the underlying mechanisms revealed that SphK2−/− MDSCs exhibit reduced expression of various suppressive molecules like arginase 1, TGF-β and STAT3. Additionally, SphK2−/− MDSCs also displayed reduced expression of HIF-1α - that in turn regulates MDSC suppressive function and metabolic commitment. Thus, intracellular level of S1P acts as an important signaling mediator regulating the suppressive potential of MDSCs. Our study unveils an important therapeutic potential of inhibiting SphK2/S1P axis in regulating MDSCs functionality to improve T cell mediated tumor control.
Potential Role of the 15kDa Selenoprotein in Colorectal Inflammation
Authors: Peters Kristin M , Carlson Bradley A , Canter Jessica E , Tobe Ryuta , Seifried Harold E , Yu Yunkai , Cao Liang , Gladyshev Vadim N , Davis Cindy D , Hatfield Dolph L , Tsuji Petra A 
Published: January 2023

Abstract
Previously, systemic knockout (KO) of the ER-resident 15kDa selenoprotein (Sep15, SelenoF) protected mice against the formation of chemically-induced pre-neoplastic lesions and suggested modulation of inflammatory pathways. Our objective is to elucidate the potential role of SelenoF in the early steps of colon tumorigenesis by assaying gene expression of KO mice and littermate controls (WT) that were either treated with 2% dextran sulfate sodium (DSS) to induce colitis or given water (control). Based on previous results, we hypothesize that SelenoF expression is inversely correlated with a protective interferon (IFN)-γ pro-inflammatory response. Microarray analyses of colonic mucosa suggest that knockout of SelenoF expression itself caused more significant gene expression changes than DSS treatment (inflammation). Gene pathway analyses indicated galectin-6 was the highest up-regulated gene in DSS-treated (133-fold) and untreated (30-fold) KO compared to WT mice. The top significantly changed network included genes involved in the differentiation of T-lymphocytes. Colonic gene expression changes in SelenoF-KO mice, as validated with qPCR, included up-regulation of guanylate-binding protein 1 (p=0.004), and a down-regulation of T-box transcription factor 21 (p=0.08). Interestingly, a decrease in IFN-γ levels (p=0.026) was detected in the serum of KO compared to WT mice, whereas the opposite trend was shown in colonic mucosa. Thus, our preliminary analyses indicate that SelenoF may indeed influence the expression of inflammatory genes in the colon. Its contribution to the regulation of colitis will continue to be elucidated.
Emergence of inflammatory Treg in premature fetal Rhesus macaques in a model of LPS-induced chorioamnionitis
Authors: Jackson Courtney , Rueda Cesar M. , Presicce Pietro , Jobe Alan H. , Kallapur Suhas G. , Chougnet Claire A. 
Published: January 2023

Abstract
Placental inflammation, termed chorioamnionitis (chorio) is one of the largest contributors to premature birth, and has been associated with several complications post-birth, mainly pulmonary and cerebral. However, a full understanding of the fetal responses to the inflammatory milieu created by chorio remains limited. To address this question, we developed an experimental model of chorio in which intra-amniotic (IA) injection of LPS in pregnant Rhesus macaques lead to inflammation of the placenta similar to what is described in human chorio. In this model of fetal inflammation, fetal splenic regulatory T cells (Treg) frequency decreased, but CD4+IL-17+ cells increased. IL-17 and other pro-inflammatory cytokines (IL-2, IL-8, IFNγ) were mainly expressed by a subset of FoxP3+ T cells that also had a low expression of Helios, thus exhibiting characteristics of “inflammatory Treg”. Several pro-inflammatory cytokines, notably TNFα and IL-1 are elevated in the cord blood and amniotic fluid of LPS exposed neonates. IL-1 receptor antagonist (IL-1RA) and anti-TNFα decreased the frequency of splenic inflammatory Treg; however, they did not normalize overall Treg frequency. Collectively, our results show that in-utero exposure to inflammation triggers a rapid pro-inflammatory response in the fetus, particularly affecting Treg frequency and phenotype, and cytokines like IL-1 and TNFα are important for many of these pathways. Due to the role of Treg in maintaining immune homeostasis, altered Treg frequency and phenotype in response to in-utero inflammation potentially contributes to the detrimental outcomes of these neonates.
A rare subset of skin-tropic regulatory T cells expressing Il10/Gzmb inhibits the cutaneous immune response
Authors: Tomura Michio , Ikebuchi Ryoyo , Teraguchi Shunsuke , Vandenbon Alexis , Francis Shand H.W. , Honda Tetsuya 
Published: January 2023

Abstract
We reported that Foxp3+ regulatory T cells (Tregs) migrating from the skin to the draining lymph node have a strong immunosuppressive effect on contact hypersensitivity (CHS) response. However, the Treg subsets that regulate the CHS response remain poorly defined.
In this study, we used a combination of single-cell real-time PCR high-dimensional gene expression profiling data with spatiotemporal information about cellular movement from the mice expressing the photoconvertible protein KikGR to elucidate the role and characteristics of Treg subsets in CHS response. We found that although immunosuppressive genes Ctla4 and Tgfb1 were expressed in the majority of Tregs, Il10-expressing Tregs were rare and unexpectedly, the majority of Il10-expressing Tregs co-expressed Gzmb and displayed Th1-skewing. Furthermore, Gzmb-/Il10-expressing Treg subsets expressed the novel markers CD43 and CCR5. CD43+ CCR5+ CXCR3− Tregs highly expressed skin-tropic chemokine receptors CCR4 and CCR8. We also measured the retention of Treg subsets within inflamed skin using KikGR mice, and found that the subset of Tregs that was most highly retained in the skin, CD43+ CCR5+ CXCR3− Tregs, had superior in vivo inhibitory function to other Treg subsets. These results suggested that even if only present in small numbers, highly activated Tregs that co-express Gzmb and Il10 and that have the capacity to remain in inflamed tissue are likely to be clinically relevant due to the role of these molecules in the control of excessive immune responses.
Taken together, the identification of a rare Treg subset co-expressing multiple immunosuppressive molecules and having tissue-remaining capacity offers a novel strategy for the control of skin inflammatory responses.
Contribution of the immunoproteasome to the inflammatory phenotype observed in obese mice
Authors: Kimura Hiroaki , Karasawa Tadayoshi , Watanabe Sachiko , Suzuki Koichi , Caturegli Patrizio , Takahashi Masafumi 
Published: January 2023

Abstract
The immunoproteasome, a proteolytic machinery derived from the constitutive proteasome expressed predominantly in immune cells, plays a critical role in the regulation of T cell polarization that occurs in autoimmune and inflammatory diseases. Recently, it has been shown that inflammation contributes to the development of obesity and metabolic disorders. We found that LMP7, one of subunits in the immunoproteasome, is expressed in epididymal adipose tissue of obese mice. In this study, we assessed the role of LMP7 in the pathogenesis of murine obesity induced by high-fat diet (HFD). LMP7 deficiency conveyed resistant to obesity, and improved glucose intolerance and insulin sensitivity. Using bone marrow-transferred chimera, we found that LMP7 contributed to the development of obesity through involvement of both bone marrow- and non-bone marrow-derived cells. LMP7 deficiency decreased inflammatory responses, such as macrophage infiltration and chemokine expression, as well as increased serum adiponectin levels and decreased serum leptin levels. Overall, LMP7 deficiency in both bone marrow- and non-bone marrow-derived cells contributed to the suppression of the inflammatory responses in the HFD-induced obesity. We propose the immunoproteasome as a therapeutic target in inflammatory disorders.
Distinct Myeloid Cell Subsets Promote Angiogenesis and Damaged Tissue Clearance Following Mild Traumatic Brain Injury
Authors: Russo Matthew V , McGavern Dorian B 
Published: January 2023

Abstract
Mild traumatic brain injury (mTBI) leads to a robust immune response featuring resident microglia/macrophages and recruitment of peripherally-derived monocytes/macrophages. We sought novel insights into the dynamics and function of innate myeloid cells following brain injury by studying a closed-skull focal contusion model of mTBI that permits real-time imaging by intravital two-photon microscopy (TPM). TPM studies of CX3CR1GFP/+ CCR2RFP/+ reporter mice revealed an early microglia response followed by CCR2+ monocytes and CX3CR1+ macrophages that accumulated 1 to 7 days post-TBI. This transition coincided with dynamic changes in gene expression that shifted from pro-inflammatory to wound-healing. Early cell death and vascular destruction led to an impressive re-vascularization of the lesioned meninges, with 80–100% wound closure observed within 7 days of injury. We used histo-cytometry to define the anatomical position of the different myeloid subpopulations within the injured meninges during the repair phase. This revealed the presence of non-classical and resident macrophages that highly expressed the remodeling enzyme matrix metalloproteinase 2 (Mmp2) in the lesion core. Depletion of neutrophils and classical monocytes increased pathology due to inefficient dead cell clearance, but re-vascularization of the wound was not affected. Interestingly, vascular regeneration was significantly impaired only when non-classical monocytes and resident meningeal macrophages were depleted, resulting in reduced numbers of CD206+macrophages in the lesion. These studies demonstrate that neutrophils, monocytes, and resident macrophages participate in coordinated yet divergent wound-healing responses to mTBI.
Development of a humanized mouse model that recapitulates the fibrotic response to biomaterial implants
Authors: Doloff Joshua C , Sadraei Atieh , Farah Shady , Bortell Rita , Brehm Michael A , Greiner Dale L , Anderson Daniel , Langer Robert 
Published: January 2023

Abstract
Implanted biomedical devices reside within tens of millions of patients in the United States alone, and are involved in millions of new surgeries every year. They comprise a major component of modern medicine and are essential for many clinical applications ranging from hip/knee replacement, tissue repair/reconstruction, controlled release, sensing, and cell transplantation. Limiting therapeutic performance and lifespan, immune-mediated foreign body rejection results in sequestration behind dense layers of fibrotic scar tissue. Current approaches for management of long-term biomedical device implantation often involve broad-spectrum anti-inflammatories. However, these agents are not specific to individual immune populations, and have side effects in vivo. To avoid such issues, improved biomaterials need to be identified with reduced immunogenicity. Deeper understanding of immune-mediated foreign body responses was leveraged to generate a variant of the humanized mouse model, previously unreported in the field of host rejection of biomaterial implants, that is capable of recapitulating fibrosis. Here, we present this model in comparison to wildtype systems, including rodents and non-human primates. Cellular and cytokine responses were determined with numerous biomaterials—hydrogel alginate, ceramic glass, and polymer polystyrene, across multiple implant sites. This model allows us to investigate human immune cells interacting directly with implantables, without putting patients at risk. It is our hope this model can be used as a pre-clinical diagnostic tool for screening implantable synthetic as well as natural materials for immunogenicity.
Invariant NKT cells recruit CD103+ dendritic cells via XCL1-XCR1 axis, thereby promoting allergic airway resistance
Authors: Woo Yeon Duk Chris , Kim Hye Young , Chung Doo Hyun 
Published: January 2023

Abstract
Among immune cells, dendritic cells (DC) and invariant (i) NKT cells are critically implicated in allergic asthma. However, the interaction between two subsets remains elusive in asthma. To address this, we investigated how these two subsets interact and exert regulatory effects on asthma. Upon intranasal inoculation of WT mice with synthetic ligand, a-galactosyl ceramide (a-GalCer), CD103+ DCs were significantly recruited into the lungs in WT but not CD1d KO mice, suggesting that iNKT cells contribute to recruiting CD103+ DCs in the respiratory system. Moreover, microarray assay revealed that iNKT cells highly expressed XCL1, a chemokine for CD103+ DCs expressing XCR1. Consistently, a-GalCer treatment increased production of XCL1 by iNKT cells in vitro and in vivo, and XCL1 KO mice showed a deficiency in iNKT cell-mediated recruitment of CD103+ DCs into the lungs. In the OVA-induced allergic asthma model, XCL1 KO mice attenuated airway resistance, inflammation, CD103+ DC number, and Th2 type immune responses in the lungs. Furthermore, adoptive transfer of XCL1-deficient iNKT cells did not alter airway resistance and recruit CD103+ DCs in CD1d KO mice, whereas WT iNKT cells or CD103+ DCs restored allergic asthma. Taken together, this study demonstrates that iNKT cells crosstalk CD103+ DCs via XCL1-XCR1 axis, thereby promoting allergic asthma.