bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue resident memory T cell responses to RSV infection are reduced in infant mice compared to adults
Authors: Lipp Madeline Anne , Eichinger Katherine M , Kosanovich Jessica L , Empey Kerry M 
Published: February 2023

Abstract
Tissue resident memory T cells (TRMs) are an important yet incompletely understood cell population that enhance the clearance of respiratory syncytial virus (RSV) infection in both humans and animal models of disease. Limited data in an influenza model of disease suggests the establishment of TRMs in infants is impaired, but the establishment of TRMs during infant RSV infection is unknown. The purpose of this study was to characterize the quantity and function of infant TRM responses to RSV infection. To address this, BALB/c mice were infected with RSV as 10-day old mice or as 6–8-week-old adults. Peripheral T cells were then depleted using FTY720 at the time of an RSV re-challenge 4–5 weeks later. TRM response was evaluated using flow cytometry; viral titers and histological staining were used to assess disease outcomes. Mice infected as infants had significantly lower total numbers of CD4+ and CD8+ TRMs compared to those infected as adults. Furthermore, TRMs established in infancy showed a Th2-biased response, with increased production of IL-4 and IL-10 compared to adults, while adult TRMs produced more granzyme B from CD8+ cells and increased IFNγ from both CD4+ and CD8+ T cells. Mice infected in infancy also showed increased %PAS positive airways compared to those infected initially as adults, suggesting more severe RSV disease. In conclusion, infants have reduced ability to establish TRMs following RSV infection and their TRM population exhibits Th2 skewing. Further studies are needed to elucidate the mechanisms that prevent effective establishment of TRMs following infant pulmonary infections.
Blocking of CA-MSC-induced desmoplasia reprograms the tumor immune microenvironment and enhances cancer immunotherapy
Authors: Cascio Sandra , Chandler Chelsea , Zhang Linan , Sinno Sarah , Bruno Tullia , Osmanbeyoglu Hatice , Vlad Anda , Coffman Lan , Buckanovich Ronald 
Published: February 2023

Abstract
Cancer associated MSCs (CA-MSCs) are multipotent stromal cells that generate tumor desmoplasia and promote tumor growth. Here, we investigated the impact of CA-MSCs on the ovarian tumor immune microenvironment. In vitro and in vivo analyses confirmed that CA-MSCs secrete numerous cytokines and chemokines, including Ccl2, Cx3cl1 and Tgfb1, that are known to induce the recruitment of monocytes into the tumor and promote macrophage immunosuppressive phenotype. Using a syngeneic and immune responsive murine ovarian tumor model, we found that CA-MSCs restrict the intra-tumoral trafficking of CD8+ T cells and inhibit the response to immune checkpoint inhibitor therapy. Similarly, in patient samples the presence of CA-MSC is inversely correlated with CD8+ T cell infiltration into tumor islets. Single cell RNAseq analyses revealed that tumoral monocytes and macrophages of a-PD-L1 treated-CA-MSCs enriched tumors express high levels of the protein transforming growth factor beta induced (Tgfbi). In ovarian cancer patient samples TGFBI is primarily expressed in the desmoplastic stroma and correlated with poor prognosis. Importantly, we found that hedgehog signaling inhibitor (HHi) therapy reversed CA-MSC driven tumor desmoplasia, reduced the number of tumor-associated myeloid cells and decreased their expression of Tgfbi. These events restored the infiltration and activation of CD8+ T cells into the tumor islets and response to a-PDL1 therapy. We are currently evaluating the role of Tgfbi in the regulation of innate and adaptive immune response. Our findings demonstrated CA-MSCs critically regulate anti-tumor immunity and support HHi as an adjunct to anti-PDL1 therapy to increase repose to immune therapy in ovarian cancer.
M2 macrophages, B cells, and PD-L1 immune checkpoint protein exhibit sexual dimorphism in the outcomes of non-muscle invasive bladder cancer
Authors: Chenard Stephen , Jackson Chelsea , Vidotto Thiago , Chen Lina , Hardy Celine , Jamaspishvilli Tamara , Berman David , Siemens D. Robert , Koti Madhuri 
Published: February 2023

Abstract
Non-muscle-invasive bladder cancer (NMIBC) is more than three times as common in men as it is in women. However, female patients with NMIBC do not respond as well to immunotherapeutic treatments and experience worse clinical outcomes than their male counterparts. The underlying causes of these discrepancies have yet to be fully elucidated.
We hypothesized that sexual dimorphism in the tumor immune microenvironment (TIME) may contribute to the inferior clinical outcomes observed in female patients with NMIBC. To test this hypothesis, we investigated immune-associated gene expression in tumors from male (n=357) and female (n=103) patients. High-grade tumors from female patients exhibited significantly increased expression of B cell-associated genes CD40 and CXCL13, and the immune checkpoint genes CTLA4, PDCD1, LAG3, and ICOS.
Based on these differences, we utilized multiplexed immunofluorescence to evaluate the density and spatial distribution of 12 immune cell markers (CD79a, CD3, CD8, FoxP3, Ki67, CD103, CD163, GATA3, CK5, IDO1, PD-1, and PD-L1) in tumors from an independent cohort of 332 patients with NMIBC (n=259 males and n=73 females). Tumors from female patients showed significantly higher infiltration of PD-L1+ cells and CD163+ M2-like macrophages compared to tumors from male patients. Notably, increased abundance of CD163+ macrophages and CD79a+ B cells were independently associated with decreased recurrence-free survival.
This study has the potential to inform the rational utilization of immunomodulatory treatments for NMIBC based on the TIME of both male and female patients. Furthermore, these novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials.
The Tumor Microenvironment Enhances Treg Fitness through Upregulation of a Foxp3-specific Deubiquitinase Module
Authors: Montauti Elena , Weinberg Samuel E , Chaudhuri Shuvam , Fang Deyu 
Published: February 2023

Abstract
Through abnormal vascularization, cytokine production, and nutrient depletion, tumors can create a highly immunosuppressive microenvironment that favors the functionality of immune regulatory programs over anti-tumor effector responses. Particularly, the highly immunosuppressive tumor microenvironment (TME) favors T regulatory (Treg) cell stability and function, while diminishing the anti-tumor activity of effector T cells. Here, we characterized previously unknown TME-specific cellular and molecular mechanisms that promote intratumoral Treg adaptation through Foxp3. We uncovered the critical role of FOXP3-targeting deubiquitinases, ubiquitin specific peptidase 22 (Usp22) and 21 (Usp21) as environmentally sensitive factors of multiple TME-specific environmental stressors including TGF-β, hypoxia, and nutrient deprivation. Specifically, Usp22 and Usp21 maintain optimal Foxp3 expression through HIF, AMPK, and mTOR activity. The simultaneous loss of both USPs synergizes to alter Treg metabolic signatures and impair suppressive mechanisms, resulting in enhanced anti-tumor activity. Our findings unveil new mechanisms underlying the functional uniqueness of intratumoral Treg cells, and identify Usp22 and Usp21 as a antitumor therapeutic targets that inhibit Treg adaptability in the TME.
ILC2-driven innate immune checkpoint mechanism antagonizes NK cell anti-metastatic function in the lung.
Authors: Halim Timotheus You Fu , Schuijs Martijn , Png Shaun , Richard Arianne , Tsyben Anastasia , Hamm Gregory , Stockis Julie , Garcia Celine , Pinaud Silvain , Nichols Ashley , Romero-Ros Xavier , Shields Jacqueline , Cohen E. Suzanne , McKenzie Andrew , Goodwin Richard , Su Jing , Eldridge Matthew , Riedel Angela , Serrao Eva , Brindle Kevin , Marioni John 
Published: February 2023

Abstract
Metastasis constitutes the primary cause of cancer-related deaths, with the lung being a commonly affected organ. We found that activation of lung-resident group 2 innate lymphoid cells (ILC2s) orchestrated suppression of natural killer (NK) cell-mediated innate antitumor immunity, leading to increased lung metastases and mortality. Using multiple models of lung metastasis, we show that interleukin (IL)-33-dependent ILC2 activation in the lung is involved centrally in promoting tumor burden. ILC2-driven innate type 2 inflammation is accompanied by profound local suppression of interferon-γ production and cytotoxic function of lung NK cells. ILC2-dependent suppression of NK cells is elaborated via an innate regulatory mechanism, which is reliant on IL-5-induced lung eosinophilia, ultimately limiting the metabolic fitness of NK cells. Single-cell and bulk transcriptomic analysis of lung NK cells reveals that post-transcriptional regulation likely accounts for IL-33-ILC2 dependent suppression of NK cell function. Using mass-spectrometry imaging (MSI) of the lungs of 13 C-Glucose infused mice, and metabolite profiling of ex vivo lung cultures, we find that IL-33 drives localized depletion of glucose via ILC2-dependent recruitment of highly glycolytic eosinophils, which can directly suppress lung NK cell function. Therapeutic targeting of IL-33 or IL-5 reversed NK cell suppression and alleviated cancer burden. Thus, we reveal an important function of IL-33 and ILC2s in promoting tumor metastasis via their capacity to suppress innate type 1 immunity.
Global inhibition of the interaction of NK inhibitory receptors with MHC-I augments coordinated innate and adaptive immunity against cancer metastasis.
Authors: Panda Abir Kumar , Sinha Surajit , Natarajan Kannan , Hernandez Jonathan M. , Margulies David H. , Shevach Ethan M. 
Published: February 2023

Abstract
Natural Killer (NK) cells are innate lymphocytes involved in the first line of immune defense and T cell adaptive immunity against viral infection and cancer, including metastasis. While on patrol, NK cells contact other cells and recognize MHC-I Ags via stochastically expressed MHC-I–specific inhibitory receptors (Ly49s in mice and KIRs in humans) that prevent NK cell activation via cytoplasmic ITIM. The binding site on MHC-Class-I for Ly49 inhibitory receptors is distinct from that for TCRs. The loss of MHC-I expression on tumor cells (“missing self”) abrogates inhibitory signals, resulting in NK activation. Global inhibition of the NK inhibitory receptor interactions in vivo by a pan-anti-MHC-I monoclonal antibody markedly activated IFNg-producing NK cells, independent of Fc receptors. NK cell-derived IFNg, along with other cytokines (MCSF & FLT3L), primed APC to induce IL-12/-15/-18/-21 cytokine cascades and enhanced levels of MHC-I and MHC-II expression that further drove the proliferation of NK cells and memory phenotype (MP) T cells. The global disruption of NK cell/MHC-I interactions significantly enhanced Th1 type signature transcription factors (Tbet & Eomes), cytokines (IFNg & Granzyme B), and chemokine receptors (CXCR3) on NK and MP T cells. Administration of pan-anti-MHC-I to unmanipulated mice profoundly augmented innate and adaptive immunity against viral infection, PD1-resistant transplanted tumors, and successfully constrained lung and liver metastasis, and protected the animals from tumor burden. Moreover, in vitro enhancement of human NK cell proliferation by a pan-anti-HLA Mab suggests that pan-anti-HLA could be a promising therapeutic strategy against chronic viral infection and cancer metastasis.
CD122-SELECTIVE IL-2 COMPLEXES TREAT OVARIAN CARCINOMAS, INDUCE TREG FRAGILITY AND PROMOTE T CELL STEM CELLS
Authors: Deng Yilun , Drerup Justin Michael , Zhang Xinyue , Reyes Ryan M , Mendez Jenny , Raeber Miro E , Garcia Myrna G , Pardon Alvaro S , Gupta Harshita B. , Boyman Onur , Curiel Tyler J 
Published: February 2023

Abstract
Regulatory T cells (Treg) engage IL-2 by high affinity CD25, and anti-tumor effector T cells (Teff) use intermediate affinity CD122. We studied IL-2 complexes (IL-2c) that selectively activate CD122+ Teff over CD25+ Tregs. We found IL-2c but not aPD-L1 potently inhibits ID8agg, an aggressive mouse ovarian cancer (OC) model. IL-2c decreased ascites Treg functional markers (CD25, GranzymeB) while upregulating them on Teffs. IL-2c inhibited Treg suppressive function in ascites but not TDLN. Ascites Tregs after IL-2c showed a fragile phenotype (increased PD-1, T-bet, and IFNg with maintained FoxP3) known to contribute to better immunotherapy response. These data suggest IL-2c inhibits Treg in the ascites through inducing fragile Tregs. Neither CD8+ T cells nor gd T cells is required for IL-2c induced Treg fragility. Studies testing other populations are ongoing. CD8+TCF-1+T cell stem cells (TCSC) improve immune checkpoint blockade in many cancer types. In ID8agg tumors, IL-2c induces CD8+TCF-1+ TCSC with tumor inhibitory capacity when transferred into Rag KO mice. tSNE analysis revealed IL-2c-induced TCSC are CXCR5+PD-1− express CCR2 CXCR3 and produce TNFa, while aPD-L1 induced TCSC are CXCR5+ and PD-1+, consistent with previous reports. These data suggest IL-2c induces beneficial CD8+TCSC distinct from aPD-L1. Although aPD-L1 is not efficacious alone in ID8agg, it significantly promoted IL-2c efficacy. Mice treated with IL-2c+αPD-L1 are resistant to tumor re-challenge even 6 weeks after final dose, suggesting durable immune memory. In sum, IL-2c is a novel OC immunotherapy that targets distinct immune pathways simultaneously, including inhibiting Tregs, boosting TCSCs, and inducing immune memory when combined with aPD-L1.
CaMKK2 deletion causes increased accumulation of CD4+ TILs and an improved ratio of effector memory TILs to Tregs
Authors: Chakraborty Molly Antara , Tomaszewski William H , Polania Jessica Waibl , Racioppi Luigi , Sanchez-Perez Luis A , Gunn Michael D , Sampson John H 
Published: February 2023

Abstract

Objective
Glioblastoma (GBM) is the most lethal primary brain tumor in adults. Although immunotherapy has been successful in some cancers, it has shown limited success in GBM. This is partially due to poor T cell infiltration, and because many T cells found in tumors are either exhausted or Tregs. Re-analysis of publicly available data has shown that CaMKK2 is more highly expressed in advanced brain tumors, and high CaMKK2 expression results in worse survival outcomes in GBM. Additionally, in survival studies that we performed, CaMKK2−/− mice showed an impressive survival phenotype that was dependent on the presence of CD8+ tumor infiltrating lymphocytes (TILs). The objective of our study was to investigate what is different about T cells found in the TME of CaMKK2−/− mice, and if this can explain the observed survival benefit.

Methods
We performed flow cytometry to determine the identities of T cells found in the tumors of CaMKK2−/− and WT mice.

Results/Conclusions
Our experiments show that there was a greater percentage of CD4+ TILs relative to CD8+ TILs in CaMKK2−/− mice, and this increase in percentage was due to increased accumulation of CD4+ TILs. Additionally, we found that there was greater accumulation of CD4+ and CD8+ effector memory TILs and a greater ratio of effector memory TILs to Tregs in CaMKK2−/− mice. The increased accumulation of the CD8+ effector memory TILs is particularly interesting because it is not simply explained by an increased accumulation of cells, as is the case with the CD4+ TILs. The increased accumulation of CD4+ TILs and greater ratio of effector memory TILs to Tregs is expected to have an anti-tumor effect. These findings make CaMKK2 a promising target to treat GBM.
Designing vaccines to combat cancer – an Indigenous approach
Authors: Sika-Paotonu Dianne 
Published: February 2023

Abstract
Pacific Peoples living in Aotearoa/New Zealand and the Pacific Region remain disproportionately affected by some cancers, with the growing burden of cancer globally remaining a significant health concern. Immunotherapy based therapeutic approaches hold some potential towards addressing inequitable cancer outcomes, treatment and management efforts for vulnerable communities, but requires appropriate inclusion and engagement with Pacific communities as part of the research process, consultation and understanding of the cultural context and clinical setting for vulnerable communities. This work sought to apply the use of an Indigenous Pacific framework to promote and support the potential applicability of immunotherapy based cancer research work within vulnerable communities adversely impacted by inequitable cancer outcomes. The Indigenous Pacific Kakala research framework was applied within this setting and supported engagement and research translation efforts and dissemination for researchers and Pacific communities in Aotearoa/New Zealand that was applicable, respectful, meaningful and appropriate to the cultural context for Pacific Peoples. This work highlights the importance of incorporating Indigenous frameworks to support Immunology based research work that is relevant, applicable and also appropriate within cultural settings.
The Impact of Advanced Age on Vaccine-Induced Tissue Immune Recall Responses
Authors: Scordo Julia M , Piergallini Tucker J , Headley Colwyn A , Reuter Nicole , Hodara Vida L , Gonzalez Olga , Giavedoni Luis D , Papin James F , Turner Joanne 
Published: February 2023

Abstract
Infectious diseases account for one-third of deaths in individuals over the age of 65. Vaccines are a primary tool to combat infection, yet they are less effective in the aged population. Many have focused on vaccine-induced peripheral blood responses in old age; however, work from our lab demonstrates that immune responses to vaccination and infection in the periphery and local infection site (tissue) differ. To improve health outcomes in our aged population, we must study both systemic and tissue vaccine responses. We do so using a model of Mycobacterium bovis BCG vaccination and subsequent tuberculin skin test (TST) eight weeks after vaccination in adult and aged baboons. Vaccination generates BCG-specific immune cells that are recruited to the skin upon TST challenge, which we can study in skin biopsies reflecting tissue-specific responses. Three days or one week after TST we examine BCG-specific responses in skin biopsies. We also determine BCG-induced responses in the blood to compare tissue and systemic responses. We find increased oxidation and decreased production of immune proteins in aged baboon skin at the site of TST challenge, despite no alterations in antigen-specific peripheral blood mononuclear cell (PBMC) responses between age groups. Interestingly, cell migration assays show increased migration of PBMCs from aged BCG-vaccinated baboons, reinforcing the notion that systemic responses are not altered and that study of the tissue environment is important to understand responses to antigenic challenge with older age.
Computational models of Immunity – Pertussis Boost (CMI-PB): Engaging the broader scientific community to develop predictive models of Tdap booster vaccination.
Authors: Soldevila Ferran C , Shinde Pramod , Kojima Mari , Overton James A , Ha Brendan , Greenbaum Jason , Ay Ferhat , Kleinstein Steven H , Grant Barry J , Peters Bjoern 
Published: February 2023

Abstract
Whooping cough is a contagious disease caused by Bordetella Pertussis. The introduction of an inactivated whole bacteria vaccine (wP) in the 1940s led to a dramatic decrease in cases. However, due to vaccine related side-effects, this was substituted by the acellular vaccine (aP) in the 90’s which resulted in rise in cases. In order to determine if there are differences between those primed with aP vs. wP in infancy, we created a model using longitudinal samples from aP boosted individuals as a proxy for antigen encounter in vivo. In previous research, we observed substantial variability in magnitude of vaccine-induced responses between individuals regardless of their priming. Yet, we identified a systematic increase of Th2 polarization of T cells at day 7, a higher expression of CCL3 in PBMC on day 3 post-boost, and an increase of IgG4 antibody polarization in aP individuals. It is not clear how these different observations are interlinked.
We hope to address this question in our project, Computational Models of Immunity – Pertussis Boost (CMI-PB). We are establishing a website that will release omics data (10 aP vs 10 wP infancy primed donors) and engage students with educational materials, and help organize a yearly contest with the broader scientific community to help develop predictive models of immunity. This study will identify the key factors responsible for the differences between aP and wP primed individuals, while also providing a model for general vaccinology.
Integrin αvβ3 limits TLR signaling in plasmacytoid dendritic cells to prevent autoimmunity.
Authors: Lorant Alina K , Lacy-Hulbert Adam 
Published: February 2023

Abstract
SLE is a chronic, systemic autoimmune disease affecting millions of people worldwide. SLE is caused by a breakdown of tolerance to self-derived nucleic acids (NA) and characterized by the presence of autoantibodies to DNA/RNA. Plasmacytoid dendritic cells (pDCs) are highly tuned to respond to NA and express a range of receptors for RNA and DNA, including TLRs 7 and 9. Following TLR engagement, pDCs produce high levels of type I interferon (IFN-I), which promotes loss of tolerance, implicating pDCs in development of autoimmunity. However, relatively little is known about how innate immune signaling is regulated in pDCs, and particularly how they distinguish self-derived from foreign NA.
TLRs 7 and 9 are both localized in endosomal compartments, and their NA ligands must be internalized and processed before they can bind. One source of these NA is dying cells and loss of their receptors is associated with SLE. We studied the role of an apoptotic cell receptor, Integrin αvβ3, in TLR signaling of pDCs and found that αvβ3 limits IFN-I production. αvβ3-knockout pDCs show increased TLR signaling and produce more IFN-I and inflammatory cytokines when stimulated in culture. In mice without αvβ3, there is a systemic increase in circulating ISGs and IFN-I after TLR7 stimulation. This corresponds with an increase in pDC activation and a decrease in marginal zone B cells, indicating elevated IFN-I production.
These data indicate αvβ3 has a pDC-intrinsic role in limiting TLR signaling, which we propose is through activation of non-canonical autophagy. Based on these data, we hypothesize that co-receptors involved in capture and internalization of nucleic acids provide contextual ‘cues’ to regulate TLR signaling and prevent autoimmunity.