bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-associated myeloid cells support T-ALL survival and proliferation through close contact
Authors: Lyu Aram , Triplett Todd , Godfrey Wesley , Ehrlich Lauren I. 
Published: January 2023

Abstract
T cell acute lymphoblastic leukemia (T-ALL) is a malignancy of developing T cells. Although intensified radiation and chemotherapy have improved survival rates to ~85% in pediatric patients, these therapies are toxic, and patients who relapse have no alternative treatments. Research on the genetic mutations driving T-ALL have been extensively characterized, but despite numerous tumor-promoting genomic alterations, primary T-ALL cells require cells/signals from the tumor microenvironment (TME) to survive. We have previously reported that myeloid cells from the TME are capable of supporting survival and proliferation of T-ALL cells in vitro. Here, we report that myeloid cells are required for T-ALL tumor growth in vivo. Treatment of a transplantable murine model of T-ALL with Clodronate liposomes, which deplete myeloid cells, resulted in a significant reduction in tumor burden in multiple tissues compared to control-treated mice. Because the myeloid compartment is heterogeneous, we assessed the capacity of purified myeloid subsets to support the survival of T-ALL cells, and identified several myeloid cell types capable of providing tumor support. To address the mechanism by which these tumor-associated myeloid cells support T-ALL growth, we performed transwell assays and found that T-ALL cells require close contact with myeloid cells to receive survival signals. We report on recent functional experiments, implicating VCAM-1 and ICAM-1 as important mediators of myeloid support of T-ALL. Future studies aim to provide further insight into the cell types and mechanisms by which stroma from the TME of distinct organs promote T-ALL survival, with the ultimate goal of developing effective therapeutics.
Tumor cell-intrinsic MHC class II expression as a determinant of immunotherapy responsiveness in an orthotopic mouse model of non-small cell lung cancer
Authors: Clambey Eric T. , Johnson Amber M. , Neuwelt Alex , Kimball Abigail K. , Kaspar Rachael , Bullock Bonnie , Kwak Jeff , Poczobutt Joanna , Li Howard , Nemenoff Raphael 
Published: January 2023

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide and the second most common cancer among both men and women in the United States. Immunotherapy regimens that disrupt the inhibitory PD-1/PD-L1 axis have recently emerged as promising treatments that can unleash anti-tumor immunity against a wide range of cancers, including a subset of lung cancers. How these therapies elicit potent anti-tumor immunity remains controversial, with markers for immunotherapy-sensitivity still an active area of investigation. To study determinants of lung cancer growth in vivo we studied two orthotopic mouse models of non-small cell lung cancer (NSCLC). These Kras-mutant tumor lines dramatically differ in their response to immunotherapy: CMT167 tumor cells are exquisitely susceptible to PD-1/PD-L1 targeted immunotherapy whereas LLC tumor cells are immunotherapy-resistant. Immunotherapy-sensitive cells showed induction of the MHC class II antigen processing and presentation pathway in vitro and in vivo, and were capable of stimulating CD4 T cells directly in ex vivo co-culture. To study the impact of tumor cell-intrinsic MHC class II induction, we used RNA interference to knockdown CIITA, a transcriptional inducer of the MHC class II pathway. CIITA knockdown in immunotherapy-sensitive cells impaired the induction of tumor cell-intrinsic MHC class II in vitro and abrogated CD4 T cell stimulation in co-culture. CIITA knockdown further converted tumors from immunotherapy-sensitive to immunotherapy-resistant. These studies identify tumor cell-intrinsic expression of MHC class II as a potential direct target for CD4 T cell recognition that may promote sensitivity to PD-1/PD-L1 blockade.
USP22 maintains regulatory T cells by stabilizing Foxp3 protein level and impairs anti-tumor immune response
Authors: Montauti Elena , Zhang Yusi , Fang Deyu 
Published: January 2023

Abstract
Ubiquitin-specific peptidase 22, a member of the deubiquitinase family, has been recently defined as a “cancer stem cell” marker in tumor development and progression. However, the physiological function of USP22, particularly in the immune system, remains unknown. Here, we identify USP22 as a specific deubiquitinase of Foxp3, a lineage-specifying transcription factor of regulatory T (Treg) cells. A genetic deletion in USP22 results in a dramatic reduction in FoxP3 expression levels and impairs the suppressive functions of Tregs without affecting the activation of conventional T cells. Consequently, a targeted deletion of USP22 in mice, either specifically in T cells or in Tregs, results in chronic T cell activation and the development of spontaneous autoimmune syndromes. Importantly, the impairment in Treg suppressive function of USP22-null Tregs boosts anti-tumor immunity. Collectively, our findings reveal a previously unappreciated physiological function of USP22 in maintaining Treg stability and identify USP22 as a potential target for cancer immunotherapy.
Molecular control of Treg-induced effector T cell DNA damage and senescence for tumor immunotherapy
Authors: Liu Xia , Mo Wei , Ye Jian , Li Lingyun , Hsueh Eddy C. , Hoft Daniel F. , Peng Guangyong 
Published: January 2023

Abstract
Regulatory T cells (Treg) have a critical function for the tumor immunosuppressive microenvironments. Defining the suppressive mechanisms utilized by Treg cells is critical for the development of effective strategies to treat human cancers. However, the molecular processes that occur in responder T cells that are suppressed by Treg cells remain largely unknown. We discovered that both naturally occurring Treg and tumor-derived Treg cells induce responder naïve/effector T cell senescence with potent suppressive activity. We further identified that initiation of DNA damage is critical and the main cause for the induction of responder T cell senescence and dysfunction mediated by human Treg cells. In addition, Treg-induced effector T cell DNA damage and senescence is due to the glucose competition between Treg and responder effector T cells. Furthermore, MAPK ERK1/2 and p38 signaling functionally cooperate with the transcription factors STAT1/STAT3 to control the molecular process of responder T cell senescence induced by human Treg cells. Senescent T cells have unique phenotypes, transcriptional profiles, gene regulation signatures, and active functions, distinct from that of exhausted and anergic T cells. Importantly, our in vivo studies suggest that human Treg-induced T cell senescence can be prevented via the inhibition of DNA damage response and/or STAT signaling in T-cell adoptive transfer mouse models. These studies identify novel molecular mechanisms of human Treg suppression and provide an emerging concept that targeting Treg-induced effector T cell senescence is a new checkpoint for immunotherapy against cancer and other diseases associated with Treg cells.
Unbiased testing of all single nucleotide variants specific to a tumor for anti-tumor CD8+ T cell immune response
Authors: Karandikar Sukrut Hemant , Shcheglova Tatiana V. , Hagymasi Adam T. , Brennick Cory A. , Mandoiu Ion I. , Srivastava Pramod K. 
Published: January 2023

Abstract
Neoepitopes presented in the context of MHC render tumors immunogenic. However, not all potential neoepitopes elicit immunity, and the attributes of immunogenic neoepitopes are yet to be fully defined. Based on the premise that regressing tumors must elicit T cells that recognize the true anti-tumor neoepitopes, we have developed and used here an ELISPOT based high-throughput assay that allows testing of the immunogenicity of a large number of candidate neoepitopes. Naïve C57BL/6 mice were challenged with the colorectal tumor line MC38 and treated, starting day 5 post-tumor challenge, with a checkpoint-blocking antibody, leading to the beginning of tumor regression. MC38-specific CD8+ T cell response was observed in tumor-bearing hosts with regressing tumors. Exome and transcriptome sequencing of MC38 and accompanying bioinformatic analyses have revealed &gt;800 single nucleotide variations (SNVs) in MC38. To identify the SNVs contributing to the immunogenicity of MC38, reactivity of the anti-MC38 CD8+ T cells isolated from mice with regressing tumors, towards individual peptides corresponding to each identified SNV, was tested. Indeed, CD8+ T cells against a number of mutant peptides were detected. These immunogenic mutant peptides are potential MHC I-restricted neoepitopes of MC38 and their role in tumor rejection is being tested.
Complex phenotyping of PD-1+ CD39+ exhausted CD8+ T cells in human carcinomas
Authors: Egelston Colt , Avalos Christian , Huang Yinghui , Wang Roger , Solomon Shawn , Tu Travis Y. , Simons Diana L. , Lee Peter P. 
Published: January 2023

Abstract
CD8+ T cell infiltration into solid tumors has been shown to correlate with patient prognosis in numerous carcinomas. Furthermore, response to checkpoint blockade therapies has been linked to an induction of T cell function and rescue of T cell exhaustion in patients. Expression of both PD-1 and CD39 on exhausted CD8+ T cells has been described in murine models of chronic disease and recently human carcinomas. Here we profile breast tumor, melanoma, and chronic lymphocytic leukemia (CLL) for the frequency and phenotype of exhausted CD8+ T cells. We find that the frequency of exhausted CD8+ T cells is highest in melanoma among these tumor types which may suggest correlation with mutational burden. Functional analysis of PD-1+ CD39+ cells in human tumors shows significant reduction of IFNγ, TNFα, and IL-2 production as assessed by intracellular flow cytometry. Further phenotyping of exhausted CD8+ T cells revealed a loss of expression of both the IL-7 receptor alpha (CD127) and KLRG1, suggesting terminal differentiation of these cells. PD-1+ CD39+ T cells also expressed CD103 suggesting potential similarities with differentiation into a peripheral resident memory phenotype. Indeed PD-1+ CD39+ exhausted T cells were only identified in peripheral tissues where cancer cells were present, such as solid tumors, tumor positive tumor draining lymph nodes, and one CLL patient, but not identified in the circulation or tumor negative tumor draining lymph nodes of patients. Finally, single cell and T cell receptor sequencing revealed distinct transcriptional and clonal signatures of PD-1+ CD39+ CD8+ T cells suggesting them to be a unique population in response to tumor antigen.
Novel T cell therapy using spherical nucleic acids
Authors: Dominguez Donye , Chernyak Natalia , Guan Monica , Long Alan , Lee Andrew , Chou Yushang , Chen Siqi , Qin Lei , Fan Jie , Mirkin Chad , Zhang Bin 
Published: January 2023

Abstract
Immune stimulating Spherical Nucleic Acids (SNAs) are nanoparticles comprised of a spherical, hollow, lipid core surrounded by an oligonucleotide shell, allowing for the simultaneous delivery of tumor antigens and immune stimulating oligonucleotides into immune cells. Interestingly, we have found that SNAs can readily enter primary nonphagocytes such as T lymphocytes. The uptake of SNAs increases expression of co-stimulatory molecules and presentation of antigen via MHC class I molecules by T cells. SNA treated T cells are endowed with the ability to prime tumor antigen specific CD8+T cells in a long lasting and durable manner compared to “free” oligonucleotide and antigen admix-treated T cells. Furthermore, SNA treated T cells are able to act as cellular chaperones and transfer both SNA-derived oligonucleotide and antigen to other cells. In an amplifying cascade manner, these “bystander” cells, which receive SNA material, then gain the ability to prime antigen-specific CD8+ T cells and achieve stronger antitumor effect. The cellular chaperone cascade only occurs when cells are treated with SNAs compared to the “free” material. The unique structural properties of SNAs thus confer a set of key biological properties that make SNAs particularly compelling for the efficient and specific delivery of tumor antigen and adjuvant in adoptive T cell therapy.
CPMA9, a newly immune checkpoint molecule, regulates T cell function
Authors: Jeon You-kyoung , Choi Inhak 
Published: January 2023

Abstract
We identified a new immune checkpoint molecule, CPMA9, belonging to the immunoglobulin superfamily (IgSF). In TCGA (The Cancer Genome Atlas) data set, CPMA9 is highly expressed and associated with poor survival in human prostate, lung, liver, breast. Also, we showed that CPMA9 differentially expressed between responder and non-responder with Pembrolizumab, PD1 blockade, treated renal cell carcinoma patients (n=49). CPMA9 inhibits TCR mediated T cell activation through suppress of proliferation, various cytokine secretion. Furthermore, hydrodynamic injection of plasmid encoding CPMA9. Ig into mice that were immunized with ovalbumin inhibits T and B cell response to chicken OVA protein. These data suggest that CPMA9 directly inhibits T cell activation as new immune checkpoint.
Neoadjuvant OX40 therapy in patients with head and neck cancer induces profound changes in tumor-infiltrating lymphocytes
Authors: Duhen Rebekka A. , Ballesteros-Merino Carmen , Bell R. Bryan , Leidner Rom , Koguchi Yoshinobu , Bifulco Carlo , Fox Bernard A. , Weinberg Andrew D. 
Published: January 2023

Abstract
OX40 is a member of the tumor necrosis factor (TNF) receptor family and, as a co-stimulatory molecule, enhances T-cell proliferation, survival and memory formation. We have also shown that it induces robust antitumor responses in patients with metastatic disease. To examine the effect of OX40 stimulation on the immune response in cancer patients, 16 head and neck squamous cell carcinoma (HNSCC) patients were enrolled in a neoadjuvant phase Ib trial and received anti-OX40 infusion 2 days, 1 week and 2 weeks prior to surgical resection.
To evaluate changes in the tumor microenvironment (TME), tissue and peripheral blood samples were obtained prior to infusion and at time of surgery. Assessment of changes in tumor infiltrating lymphocyte (TIL) and peripheral blood populations were performed by flow cytometry and fluorescent multiplex immunohistochemistry (IHC).
OX40 administration was well tolerated with low toxicity. Activation and proliferation of CD4+ and CD8+ memory T-cell populations in both the TME and periphery peaked between 12 and 19 days after OX40 infusion, as demonstrated by increased levels of Ki67, CD38 and ICOS. In the TIL, expression of CD39, ICOS and PD-1 was increased on CD4+ T cells in most patients and the frequency of tumor-reactive CD39+CD103+ CD8+ T cells was increased in some patients. IHC analysis revealed striking changes in tissue integrity and increased lymphocyte infiltrates in 4/16 patients.
With this study, we have found that neoadjuvant OX40 immunotherapy is feasible and safe in patients with HNSCC and results in robust activation and proliferation of T cells within the tumor. Based on these findings, we are now comparing the transcriptome and changes in TIL repertoire and metabolism before and after treatment.
Modulation of TFH-like cells and anti-tumor activity of immune checkpoint blockade.
Authors: Zappasodi Roberta , Budhu Sadna , Hellmann Matthew D. , Postow Michael A. , Senbabaoglu Yasin , Manne Sasikanth , Gasmi Billel , Liu Cailian , Zhong Hong , Li Yanyun , Huang Alexander C. , Hirschhorn-Cymerman Daniel , Panageas Katherine S. , Wherry E. John , Merghoub Taha , Wolchok Jedd D. 
Published: January 2023

Abstract
A significant proportion of cancer patients do not respond to immune checkpoint blockade therapy. To deepen our understanding of the mechanisms of resistance to immunotherapy, we studied a population of CD4+Foxp3− T cells expressing PD-1 (4PD1hi), which we found to be up-regulated in B16-melanoma bearing mice after CTLA-4 blockade in association with limited response to treatment. We observed that 4PD1hi accumulate intratumorally as a function of tumor burden in untreated tumor-bearing hosts. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1hiincreases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect in both B16-bearing mice and melanoma patients and significantly improves anti-tumor activity. In addition, we found that persistence of high levels of 4PD1hi after PD-1 blockade correlates with poor prognosis in melanoma patients. Mechanistically, we show that mouse and human circulating and intra-tumor 4PD1hi inhibit T-cell functions in a PD-1/PD-L1 dependent fashion. In addition, we found that mouse and human 4PD1hi resemble follicular-helper-T-cell(TFH)-like cells and that CTLA-4 blockade activity is improved in TFH deficient mice. These findings broaden our understanding of the mechanisms that limit anti-tumor immunity, providing an additional explanation for the incremental activity of combined CTLA-4 and PD-1 blockade. Our study also defines 4PD1hi as a new prognostic and pharmacodynamic biomarker for the design of optimal checkpoint blockade combination schedules and dosage.
Bacterial and viral pathogen associated molecular patterns create different early transcriptomic landscapes in bovine macrophages
Authors: Toka Felix Ngosa , Dunaway Kiera , Smaltz Felicia , Szulc-Dabrowska Lidia , Drnevich Jenny , Mielcarska Matylda Barbara , Bossowska-Nowicka Magdalena , Schweizer Matthias 
Published: January 2023

Abstract
Pathogens stimulate immune functions of dendritic cells and macrophages (MΦ). There is no clear understanding of the nature of transcriptomic changes caused in cells upon stimulation through pattern recognition receptors by various pathogens. Our study investigated the early transcriptomic changes of bovine MΦ in response to stimulation with CpG or poly I:C. BMΦ were incubated with CpG or pI:C for 6 h and RNA isolated for transcriptomic analysis by RNAseq. Bioinformatics tools were used to analyze differentially expressed genes (DE). Results showed that, of the 13740 genes mapped to the bovine genome, 2245 had p-value ≤0.05, deemed as DE. At 6 h post stimulation, pI:C induced a different transcriptomic profile from that induced by CpG. CpG upregulated 347 and downregulated 210 genes. pI:C upregulated 761 and downregulated 414 genes. The highest expressed genes in both stimulations belonged to the TNF superfamily, TNFSF18 (CpG) and TNFSF10 (pI:C) and in both cases the lowest downregulated gene was CYP1A1. CpG induced canonical pathways that are unrelated to immune response in BMΦ in contrast to pI:C which induced canonical pathways directly related to antiviral immune functions dominated by IFN signalling genes. The transcriptomic profile after pI:C stimulation was consistent with TLR3 signalling. CpG influenced expression of genes involved in molecular and cellular functions in free radical scavenging. We conclude that CpG and pI:C induce different early transcriptional landscapes in BMΦ line, but each suited to a specific function of BMΦ during interaction with pathogens.
Association between bovine viral diarrhea virus load in subsets of peripheral blood mononuclear cells (PBMC) in persistently infected animals and health outcome
Authors: Falkenberg Shollie M. , Dassanayake Rohana , Walz Paul , Neill John , Ridpath Julia 
Published: January 2023

Abstract
Bovine viral diarrhea virus (BVDV) can cause acute and persistent infections. BVDV acute infection results in generalized immunosuppression characterized by lymphocytopenia typically associated with depletion of CD4+ and CD8+ T cells. BVDV persistent infection is the result of immune tolerance and is not associated with lymphocytopenia. The health outcome of persistently infected (PI) calves varies widely; some die of mucosal disease, some succumb to ill thrift and others survive to adulthood. Detection of BVDV at the single lymphoid cell level is important to the study of subsets of PBMC in acute and persistent infections, however there are few methods available for the detection and quantification of BVDV at the single cell level. To circumvent this difficulty, a novel PrimeFlow RNA assay using in-situ detection of BVDV was developed. This assay was used to evaluate differences in viral distribution within subsets of PBMC over time in PI calves carrying one of two different species of BVDV (type 1 and type 2). Calves were sampled at 3 different time points at least one month apart. During the course of the study, a subset of the calves died from ill thrift. Mucosal disease was not indicated in any of the deaths. Using RNA probes specific for the BVDV Npro-Erns coding region for each respective virus, BVDV RNA was detected in all PBMC of PI that appeared clinically healthy. Calves that succumbed to ill thrift were found to have no or little virus in T cells. The clearance of virus from T cells suggests a breakdown in immune tolerance in these calves. This is the first report of an association between viral load in the T cell populations and survival in PI calves.
Dietary supplementation of Allium hookeri improved intestinal immune response on necrotic enteritis of young broiler chickens
Authors: Lee Sung Hyen , Lee Youngsub , Lillehoj Hyun S. , Kim Jung-Bong , Jang Hwan-Hee , Hwang Kyung-Ah , Choe Jung-Suk , Kim Dong-Wook 
Published: January 2023

Abstract
This study was conducted to evaluate the effects of dietary Allium hookeri on intestinal immune response of young broiler chickens induced with necrotic enteritis (NE). One hundred fifty birds (1 day old) were randomly assigned to 6 groups (n =25 birds/treatment) and fed a basal diet (control) or basal diet supplemented with Allium hookeri (AH) root at 1 or 3% of the basal diet; AH1 and AH3, respectively. Birds were orally challenged with E. maxima 41A (1 × 104 cells/chicken) on day14 and followed by C. perfringens infection (1 × 109 CFU/chicken) on day18. NE-associated infection and intestinal immune response were assessed by average body weight gain, lesion score and oocyst shedding. The effect of dietary supplementation with AH on transcript levels of pro-inflammatory cytokines, tight junction and mucin protein in the jejunum were quantified by qRT-PCR. At day 20, the birds fed 3 % of AH in diet (AH3) significantly weighted more than the control group though the NE-challenge significantly reduced average body weight gain compared to the uninfected control group. Among the NE-challenged groups, gut lesion score and oocyst shedding significantly decreased in the birds given with AH (1 or 3%) compared to the control group. Gene expression levels of pro-inflammatory cytokines IL-8, IL-17α, and LITAF decreased in AH3 groups compared to the infected control group though the levels significantly increased in the NE infected groups. Interestingly AH significantly increased transcript levels of intestinal tight junction proteins and mucin at 1% of diet, not 3% of diet. These results suggest that dietary supplementation of AH can improve chicken health by controling immune response against NE and it depends on the dietary level of AH.