bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigen-specific CD4 T cell polarization is altered by immune checkpoint blockade in pancreatic ductal adenocarcinoma
Authors: Cruz Eduardo , Burrack Adam L , Miller Ebony , Stromnes Ingunn 
Published: August 2023

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with poor response to conventional immune checkpoint inhibitors. Early data by our group suggests CD4 T cell depletion abrogates response to a novel combination therapy that is transiently curative in a murine model of PDA. Given the importance of CD4 T cells in PDA control, we now seek to describe CD4 T cell dynamics in PDA at an antigen-specific resolution. To this end, we developed a novel tetramer reagent towards a recently identified MHC class II model epitope. Through this, we observe antigen-specific T-cell polarization that is distinct from the bulk CD4 population both in the spleen and in the tumor microenvironment. Tumor-specific CD4 T cells also displayed differential polarization during combination therapy, suggesting positive response to therapy is mediated in part by TCR-dependent stimulation of the CD4 compartment.
Exogenous catalase treatment enhances CD8+ T cell functionality and hinders T cell exhaustion
Authors: Shah Rushil H , Aksoylar Halil-Ibrahim , Pal Rinku , Boussiotis Vassiliki A , Patsoukis Nikolaos 
Published: August 2023

Abstract
ROS are small short-lived oxygen-containing molecules which are highly chemically reactive and involved in the regulation of biological processes like T cell activation and proliferation. The tumor microenvironment (TME) is a metabolically hostile environment with a deficiency in nutrients like glucose and glutamine, accumulation of tumor-driven metabolic waste, and extreme hypoxia. Hypoxia results in impaired mitochondrial function and generation of excess levels of ROS, which have been known to promote T cell exhaustion. Here, we investigated how exogenous treatment of antioxidant catalase altered CD8+ T cell effector responses and T cell exhaustion using OT-I TCR transgenic mice. During CD8+ T cell effector differentiation in vitro by stimulation with cognate antigen followed by culture with IL-2, addition of catalase significantly enhanced T cell activation and effector differentiation. Catalase-treated effector cells had higher expression of critical activation markers including CD69 and CD25, increased expression of the stemness marker TCF-1, and enhanced secretion of effector cytokines IFNγ and TNFα. During induction of T cell exhaustion in vitro by co-culture with B16 melanoma expressing ovalbumin (B16-Ova), catalase-treated OT-I T cells had significantly increased cytotoxic activity, enhanced expression of CD25 and lower co-expression of PD-1 and TIM-3 relative to non-treated OT-I T cells. Our findings uncover a new role for catalase in altering the fate of CD8+ effector T cells and potentially a new therapeutic tool for managing T cell exhaustion.
NIH (R01 CA212605)
Unique Immunoregulation of Lung Cancer by CD8+ T Cells
Authors: Kratzmeier Christina , Khalil May , Banerjee Anirban , Krupnick Alexander Sasha 
Published: August 2023

Abstract
We hypothesize that immunoregulation of lung cancer differs from that of other malignancies. To study this hypothesis in greater detail, we utilized a primary carcinogenesis model of 3-MCA-induced flank fibrosarcoma or urethane-mediated lung cancer in B6 wild-type or CD8+ T cell deficient mice. CD8+ T cell deficiency increased sarcoma tumor growth (199±65 vs. 511±138 mm3 for B6 vs B6CD8−/−mice respectively p = 0.03) but decreased the growth of lung cancer (1.7±0.2 vs. 0.6±0.13 cm3 for B6 vs B6CD8−/−mice respectively p = 0.006). We validated this surprising finding in multiple other tumor models including B16 melanoma, EG7 lymphoma and LLC lung cancer. For all non-lung cancer tumors, the presence of CD8+ T cells decreased tumor growth. In direct contrast, the presence of CD8+ T cells accelerated the growth of lung cancer. Cytokine analysis revealed a significant CD8+ T cell-dependent increase of Th-1 polarizing cytokines, IFN-γ and TNF-α, in LLC lung cancer-bearing but not B16 melanoma-bearing mice. Similar to CD8+ T cell deficiency, neutralization of IFN-γ and TNF-α in B16 melanoma-bearing mice increased tumor growth but ameliorated the growth of lung cancer. In addition, we noted an IFN-γ and TNF-α-dependent expansion of CD8+Foxp3+ T cells in the tumor infiltrating lymphocytes of lung cancer-bearing mice, but not melanoma-bearing mice. Therefore, contrary to the accepted dogma, an increase in Th-1 polarizing cytokines, mediated in some fashion by lung cancer associated CD8+ T cells, facilitates rather than ameliorates the growth of this malignancy. Our data suggests that immunoregulation of lung cancer is unique and may require novel immunomodulating strategies that may not necessarily apply to other malignancies.
This project was funded by P01 AI116501, R01 AI145108, I01BX002299
Archaeal and bacteriophage derived Cas proteins demonstrate memory T cell response in humans
Authors: Bajgain Pratima , Sauna Zuben E , Simhadri Vijaya 
Published: August 2023

Abstract
The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas system is a powerful gene editing tool with clinical applications in the pipeline. In vivo delivery of Cas proteins could induce immune responses which would limit the utility of the technology. Previously, we and others have demonstrated pre-existing immunity to Cas9 proteins derived from Staphylococcus aureus (Sa) and Streptococcus pyogenes (Sp) in human populations. As these Cas proteins are of microbial origin this finding was not surprising. There are numerous naturally occurring alternatives to Cas9 and many of these are being leveraged for gene editing. Alternatives to Cas9 that have successfully been used in gene editing technologies include Cas12a (derived from Acidaminococcus sp), Cas14a (derived from DPANN, a super-phylum of archaea) and Casϕ (derived from a huge bacteriophage). It has been postulated that humans would not have pre-existing immunity to some of these Cas proteins. In the comparative study described here, we evaluated pre-existing antibodies and memory T-cell responses to Cas9, Cas12a, Cas14a and Casϕ from the same 18 healthy donors for all proteins. Pre-existing antibodies were identified using ELISA and memory T-cell responses were measured using the ELISpot assay. All four Cas proteins tested positive for both assays in at least some donors. It has been speculated that pre-existing immunity to Cas9 proteins is due to human exposure to the pathogenic bacteria they are derived from. Consequently, Cas14a and Casϕ should not be associated with pre-existing immunity. However, our results show that anti-Cas14a and anti-Casϕ antibodies were detected in ~50% of the study population and these donors also showed memory T-cell responses.
Human Memory T cells show differential metabolic preferences
Authors: Akdogan Bagdeser , Rose James R , Rahmberg Andrew R , Scharer Christopher D , Boss Jeremy M 
Published: August 2023

Abstract
Metabolic reprogramming regulates survival and function of immune cells, including T cells. Previous studies revealed that memory T cells are quiescent populations that primarily use OXPHOS for their metabolic needs. However, antigen rechallenge induces metabolic reprogramming including the engagement of aerobic glycolysis in which glucose is converted into lactate rather than oxidized into mitochondria. Here, we compared the metabolic characteristics of human naïve and memory T cells (TCM, TEM, and TEMRA) that are characterized by the cell surface proteins CCR7, and CD45RA. T cells were enriched from human PBMC samples, and then the subsets were sorted by flow cytometry. RNA-seq libraries constructed from each population were sequenced. Comparison of metabolism related transcript levels of the subsets revealed a distinct metabolic state in each cell type. Seahorse assays, mitochondrial staining flow cytometry assays and the SCENITH (Single Cell ENergetIc metabolism by profilIng Translation inHibition) assays were performed to assess the metabolisms of the individual populations. Our data indicated that resting CD4 and CD8 memory T cell populations have higher glycolytic and fatty acid capacity than the naïve T cells, consistent with the RNA-seq data. Resting naïve T cells depend on mitochondrial ATP production more than the memory T cells. However, when the cells are stimulated, the glycolytic capacity increased in all cell types and mitochondrial dependence decreased without a significant difference between subsets. Overall, our data highlights how memory T cell subsets retain greater metabolic capacity than naive T cell, potentially contributing to more efficient secondary responses.
Lactose differentially modulates functionalities of antigen-presenting cells and T cells
Authors: Sur Meghna , Mone Kiruthiga , Zhang Guolong , Reddy Jay 
Published: August 2023

Abstract
Lactose is a milk sugar that appears to have immunomodulatory properties, but conflicting reports are available regarding its effects on inflammatory response and Treg cell functions. To delineate these aspects, we sought to test the hypothesis that lactose alters T-cell responses by modulating the functionalities of antigen-presenting cells (APCs). First, using the mouse macrophage cell line (RAW 264.7), we noted that lactose could reduce LPS-induced oxidative stress (P&gt;0.05) without altering viability. Second, while the expression of MHC class II molecule was unchanged, an inverse relationship was noted with the costimulatory molecules [downregulated CD40 (P&gt;0.005) and CD80 (P&gt;0.005), and upregulated CD86 (P&gt;0.005)], suggesting that lactose-mediated effects on APCs are heterogeneous and may involve unique regulatory elements for individual gene expression. Third, by testing the effects of lactose in the sorted mouse primary T cells, lactose moderately modulates T cell activation stimulated by anti-CD3 and anti-CD28, including IL-2 and IFN-γ production, but the cell viability was unaffected. However, upon the addition of IL-2, the reduced T cell activation was no longer apparent as evaluated by CFSE staining of CD4 and CD8 T cells, indicating that lactose’s effects on T cells may involve an IL-2-dependent mechanism. Taken together, our data support the notion that lactose could exert its effects on T cells directly or indirectly by modulating the APC functions that may have implications on health and disease.
C-terminally phosphorylated p27 drives cancer-promoting inflammation
Authors: Razavipour Seyedehfatemeh , McIntosh Alec , Bagheri Amir , Yoon Hyunho , Shin Miyoung , Van Boven Derek , Yi Chunling , Slingerland Joyce 
Published: August 2023

Abstract
p27 normally inhibits cell cycle progression and cell growth. In cancers, deregulated p27 acts as an oncogene to promote metastasis when phosphorylated by PI3K-activated kinases at T157 and T198 (p27pTpT). We showed p27pTpT transcriptionally co-activates cJun and induces STAT3 activation. Here, we pursue the hypothesis that p27pTpT transcriptionally co-activates STAT3 target genes to expand cancer stem cells (CSC) and promote cancer inflammation.
In triple negative breast cancer (TNBC) lines, we showed that p27pTpT increases stem cell properties, including sphere formation and expression of stem cell transcription factors MYC, OCT4, NANOG, and KLF4 through STAT3. ChIP-seq/RNA-seq showed p27 recruits STAT3 to gene promoters to induce profiles of p27/STAT3 co-target genes, including MYC and JAG1, that increase tumor-initiating stem cells (TISC) in vivo. This work revealed a novel role for p27pTpT as a driver of CSC expansion.
Since CSCs mediate treatment resistance, in part, by promoting inflammation, we next tested if p27pTpT drives cancer inflammation. p27/STAT3 co-target genes associate strongly with inflammatory pathways. ATAC-seq/ ChIP-seq showed p27pTpT increased chromatin accessibility to co-recruit p27/STAT3 to promoters of oncogenic, proinflammatory genes (IL-6, NF-κB/RELA, VEGFA) and to mediators of immune evasion. p27pTpT also increased STAT3 activation, p65 (NF-κB subunit), and IL-6 protein levels on WB, and increased CCL2 secretion on ELISA. Notably, both p27 knockdown and STAT3 inhibition decreased p27pTpT-driven CCL2 secretion.
Together, these data indicate that when p27 is C-terminally phosphorylated, it acquires a novel oncogenic role to promote STAT3-driven CSC expansion and cancer inflammation.
Characterization and clinical significance of T follicular helper cells in follicular lymphoma
Authors: Yang Zhi-Zhang , Tang Xinyi , Kim Hyo Jin , Mukherjee Prithviraj , Bhardwaj Vaishali , Mondello Patrizia , Ansell Stephen 
Published: August 2023

Abstract
T follicular helper (TFH) cells are a subset of CD4+ T cells that reside within the follicles of secondary lymphoid organs and play an essential role in the germinal center (GC) reaction. To examine the role TFH cells in follicular lymphoma (FL), we first characterized TFH cells using single cell analysis with the high-throughput technologies of mass cytometry (CyTOF) and the Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq). Clustering analysis revealed that TFH cells form subsets with unique phenotypes, and the expression of many common markers including CXCR5, ICOS, IL-21, TOX2, CD57, GZMK, XCL1, XCL2, CXCL13 and CD40L varies on TFH subsets. We found that TFH cells are phenotypically more heterogenous in FL than benign tonsil tissues by both proteomic (n=82) and transcriptomic (n=8) profiling. Each FL patient showed different dominant TFH subsets, in contrast to tonsil donors which were highly homogenous. Some TFH subsets were only present in FL and absent in tonsil tissues, suggesting the existence of FL-specific TFH cells. Cytokines (IL-2, IL12, IL-17 and IL-21) and activated B cells upregulated TFH markers including PD-1, CXCR5 and IL-21 to induce the development of TFH subsets such as IL-21+ or IL-21+IFN-g+ TFH cells, which was inhibited by rapamycin, an immunosuppressor. We observed that the TFH cell frequency significantly correlated with the number of lymphoma B cells. Futhermore, while TFH cells as a whole showed no correlation with prognosis, TFH subsets such as CD57+ TFH cells were significantly associated with an inferior patient outcome. Taken together, our results indicate that TFH cells are highly heterogenous with different tumor-specific TFH subsets present in FL and associated with patient outcomes in FL.
The metabolite derived from high-salt diet-induced gut microbiota modulates brain tumor environment
Authors: Kim Chae Won , Park Jang Hyun , Kim Hyun-Jin , Kang In , Lee Heung Kyu 
Published: August 2023

Abstract
The Westernized diet refers to consuming high amounts of saturated fat, sugar, and salt, and low amounts of dietary fiber. Such a diet is currently thought to contribute to non-communicable diseases such as autoimmune diseases, heart disease, and cancer. A high-salt diet (HSD) is known to affect various organs, including the cardiovascular, renal, and central nervous systems. Recently, several studies reported the effect of HSD on cancer due to the enhanced osmolarity of tumor microenvironment. However, it has been known that the concentration of sodium in brain is tightly regulated. That is, there may be another effect of HSD to tumor environment in brain. In addition, the effects of HSD on brain tumor have not been elucidated. In this study, we observed an increased tumor burden in mice who received the high-salt diet. Mice on a high-salt diet also showed a change in their gut microbiota. The specific bacteria significantly increased in HSD group compared to normal-salt diet (NSD) group. This bacteria is known to produce several metabolites, and we measured these metabolites in cecum of NSD and HSD group. Among them, the one metabolite increased in HSD group and we supplemented this metabolite to mice with brain tumor. Then, we observed the exacerbation of brain tumor post the supplement compared to control group. Therefore, we speculated that the HSD exacerbated brain tumor via the increased production of metabolite by altered gut microbiota.
Liver Metastases Potentiate Cancer Progression
Authors: Pearson Ashley N , Holcomb Erin , James Jadyn , Jungles Kassidy Mikala , Nedzesky Nicholas , Schaefer Grace , Tate Akshay , Liu Meilan , Wang Zhuwen , Huber Amanda , Green Michael 
Published: August 2023

Abstract
Metastases are the primary cause of cancer mortality, and different sites of metastasis are associated with different prognostic outcomes. In particular, liver metastases are associated with poor overall survival and increased disease progression. It is known that liver metastases suppress systemic antitumor immunity to limit immunotherapy efficacy on primary tumors through hepatic siphoning and deletion of CD8+ T cells, induction of T regulatory cells, and depletion of dendritic cells. However, it remains unclear how liver metastases promote subsequent disease progression and the metastatic cascade. To investigate how liver metastases reprogram the immune system to potentiate disease progression, we developed a preclinical polymetastatic murine model of liver and lung metastases. Using B16F10 melanoma in syngeneic C57Bl/6 mice, we observed that the presence of liver metastases increased the lung metastatic burden. We hypothesized that liver metastases potentiate the formation of a tumorigenic, immunosuppressive premetastatic niche in distant sites. We conducted single cell RNA (scRNA) sequencing and flow cytometry immune profiling of the liver, peripheral blood, and lungs of mice with or without liver metastases. Together, these data suggest an association between Ly6g+Ly6c− neutrophils and melanoma progression in mice with liver metastases. Future efforts will focus on defining the contribution of neutrophils to disease progression with the ultimate goal of understanding and addressing the immunosuppression promoted by liver metastases.
Premalignancy induced B cell-centered immune aggregates for immune-prevention against triple negative breast cancer
Authors: Zhou Xian , Zeng Jianhao , Riddick Alexys T , Engelhard Victor H , Zong Hui 
Published: August 2023

Abstract
Immune surveillance is believed to be a critical mechanism to eradicate premalignant mutant cells to prevent cancer. However, the cellular organization and mechanisms for immune surveillance remain largely unknown because premalignant mutant cells are “invisible” in patient samples and conventional animal models. To gain a glimpse into this process, our lab developed a genetically engineered mouse model recapitulating human basal-like breast cancer through unequivocal labeling of premalignant p53-Brca1 mutant cells with GFP. Using this model, we discovered prominent immune aggregates in close proximity to mutant ducts, which eventually disperse at the tumor stage. These immune aggregates manifest tertiary lymphoid structure (TLS)-like organization, enriched with activated B cells co-clustered with T cells and CD11b+ myeloid-derived cells. To fully characterize these TLS-like aggregates, we are profiling the dynamic changes in immune composition and activation status from premalignancy to malignancy. In parallel, to investigate the molecular mechanism behind their organization, we are studying the relevant chemokines, like CXCL13, and corresponding source cells. Ultimately, we plan to perform functional experiments to determine if these TLS-like structures are responsible for controlling the malignant progression of breast cancer. Our work provides direct evidence of how immune response against premalignant cells before breast cancer forms.
Supported by grants from NIH (R01CA256199-01A1)
Aging, Immunity and Cancer
Authors: Blomberg Bonnie , Frasca Daniela , Diaz Alain , Antoni Michael B 
Published: August 2023

Abstract
Our studies have shown that breast cancer patients receiving CBSM (Cognitive Behavioral Stress Management) have less stress and inflammation and better immune response, e.g. antibody response to influenza vaccine. More recently immune (B lymphocyte, antibodies) and metabolic (higher) conditions were characterized. We previously showed the stress reduction group had better long term (11 year) survival. Currently we are further analyzing negative and positive contributors to immune response in cancer patients including age and body mass.
Supported by grants from NIH (R01 AI)", Florida Breast Cancer and SCCC
Immune Spatial Differences Between Short and Long-term Surviving Glioblastoma Patients
Authors: Najem Hinda , McCortney Kathleen , Steffens Alicia , Tripathi Shashwat , Walshon Jordain , DeCuypere Michael G , Brandenburg Raymond , Hoerich Daniel , James Charles David , Lesniak Maciej S , Sonabend Adam M , Chandler James P , Tate Matthew , Burks Jared K , Horbinski Craig , Heimberger Amy B 
Published: August 2023

Abstract

Introduction
Immune surveillance, distribution, interactions, and antigen presentation within the tumor microenvironment (TME) may influence anti-tumor reactivity and survival.

Methods
Dichotomized newly diagnosed treatment-naïve IDH1 wild-type glioblastoma, negative MGMT promotor methylation (65%), short-term (STS; ≤ 6 months; mean age 66 years; n=10) or long-term (LTS; &gt;2 years; mean age 50 years; n=10) survivors, were profiled using high dimensional fluorescence multiplex staining spatial analysis of the TME using a panel of 26 markers.

Results
The amounts of specific immune cells (CD4+, CD8+, FOXP3+, CD11c+, CD20+, CD68+, CD205+, NKG2D+) were similar between cohorts, except STS were enriched with CD163+ expressing macrophages and LTS had more P2RY12+ microglia throughout the TME. There was minimal MHC-I expression and no difference in MHC-II on the myeloid populations (CD68+, CD11c+, CD163+, P2RY12+, and/or in combination) in both cohorts. TIM-3 was the only immune regulator substantially expressed on P2RY12+ microglia and the other myeloid populations, irrespective of survival. Perivascular clustering of CD11c+CD163+ cells was enriched in STS cases. The TME in LTS cases demonstrated adaptive immune activation processes, including CD11c+P2RY12+CD205+ microglia interacting with CD45RO− naïve, non-exhausted (PD-1−, LAG3−, Tim3−) CD8+ T cells expressing the LCK+ immune synaptic marker.

Conclusion
Immune activation interactions between CD8+ T cells and microglia in the TME may help determine STS versus LTS in GBM patients.
PLA2G2A and ANXA1 are correlated with NLRP3 in colitis-associated colorectal cancer
Authors: Yoon Chanjin , Yang Chul-Su 
Published: August 2023

Abstract
Inflammation inspires the development of cancer and contributes to all stages of tumorigenesis. Inflammatory bowel disease (IBD) is involved with an elevated risk of colitis-associated colorectal cancer (CAC). NLRP3 inflammasome is linked to progression and survival in colorectal cancer; however, the underlying NLRP3 inflammasome mechanism in CAC remains unclear. Nlrp3 mRNA is highly expressed in AOM/DSS induced-CAC. Using bioinformatics analysis, we identified candidate genes involved with CAC and NLRP3 in AOM/DSS induced-CAC mice model. These genes are altered in AOM/DSS induced-CAC compared with low-grade dysplasia and are associated with Inflammatory response. We found both Pla2g2a and Anxa1 expression are elevated in AOM/DSS induced-CAC mice and were predicted to interact with Nlrp3 in the STRING database. Furthermore, we found that Pla2g2a and Anxa1 mRNA expression is positively correlated with Nlrp3 expression in colorectal cancer tissues. Our data suggest that PLA2G2A or ANXA1 may regulate NLRP3 in CAC and provide a novel therapeutic approach to treatment.
This work was supported by the NRF grant funded by the Korea government (MSIP) (2019R1I1A2A01064237).