bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of macrophages in tumor microenvironment by microRNA in T cell lymphoma-bearing mice
Authors: Abdulla Osama Azeldeen , Nagarkatti Prakash S , Nagarkatti Mitzi 
Published: January 2023

Abstract
The tumor microenvironment is a complex niche created by cancer cells to survive and evade the immune system. Macrophages (Mϕs) are considered to be one of the most abundant cells in the cancer microenvironment. Studies have shown that cancer cells have predilection for the M2 cell phenotype compared to M1 in the microenvironment, because M2 Mϕs promote immunosuppression and subsequently enhance tumor cell proliferation and angiogenesis. The aim of this study was to compare the gene expression profile of tumor-associated Mϕs (TAMs) and splenic Mϕs from tumor-bearing hosts (TBHs) and determine the epigenetic regulation of altered genes. For this purpose, C57BL/6 mice were injected with 1×106 EL4 cancer cells subcutaneous to induce tumor growth and 10 days later, TAMs and splenic Mϕs were isolated. Cell phenotyping by flow cytometry showed that there was an increase in M2 cells in TAMs when compared to splenic Mϕs in TBHs. TAMs also exhibited increase in IL-10, IL-6, VEGFA, and ARG-1 whereas there was a decrease in the expression of MYD88, PTEN, TGFβ3 and P53 when compared to splenic Mϕs in TBHs. Analysis of the microRNA profile of the Mϕs showed differential regulation and using ingenuity pathway analysis (IPA), we found various miRs (miR-21a, miR-30a, miR-30c, miR-125b, miR-155) were upregulated. These miRs targeted MYD88, PTEN and P53, which leads to the overexpression of IL10, known to skew Mϕ polarization to an M2 phenotype. In summary, these studies demonstrate that several miRs regulate IL10 to polarize TAMs from an M1 to M2 phenotype in the tumor microenvironment. (Supported by NIH P01AT003961, P20GM103641, R01AI129788, R01 ES030144 and R01AI123947)
Altering the dendritic cell signature in the lung: a new adjuvant to immune checkpoint inhibitor therapies?
Authors: Brassard Julyanne , Bernatchez Emilie , Gill Meredith Elizabeth , Joubert Philippe , Blanchet Marie-Renée 
Published: January 2023

Abstract
Lung cancer is the leading cause of cancer-related death. While the recent introduction of immune checkpoint immunotherapies significantly improves patient outcome, many do not respond to this treatment. Dendritic cells (DCs) activate CD8+ T cells to promote the anticancer immune response. Also, in mice, pulmonary CD103+ DC1s specialize in tumour antigen presentation. However, cancer induces an immunosuppressive microenvironment that alters immune function to promote tumor development. Yet, the impact of lung tumor development on DCs remains misunderstood. To study the impact of lung tumour development on the lung dendritic cell signature, Lewis lung carcinoma (LLC) and B16F10 cells (melanoma lung metastasis) were injected intravenously, and lung DC populations analysed by flow cytometry. We observed that in cancer, the proportions of CD103+ DC1 are largely reduced, while an uncharacterized lung CD103+CD11b+ DC population is induced. The latest express surface markers and transcription factors associated with the DC2 population and high levels of PD-L1 and PD-L2 regulatory molecules. This is of crucial importance to immune checkpoint inhibitor therapies, as they rely on the efficient presentation of tumour antigen by DCs to induce T cell responses. In order to promote the anti-tumor capacity of the DC signature, CD103+ DC1s were injected in combination with an immune checkpoint inhibitor (anti-PD-1) in the B16F10 model of resistance to anti-PD1 therapy. The co-injection led to improved sensitivity to immunotherapy. Thus, promoting the replenishment of an anticancer DC environment could be an interesting therapeutic avenue to increase the efficiency of existing immune checkpoint inhibitor therapies.
Depletion of tumor-associated macrophages by melittin-dKLA enhances anti PD-L1 mediated anti-tumor effects in breast cancer models
Authors: LEE HYUNJI , KIM SO YOUNG , CHOI ILSEOB 
Published: January 2023

Abstract
Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment and known to have an M2-like pro-metastatic phenotype. M2-like TAMs directly support migration, adhesion and invasion of tumor cells. Therefore, M2-like TAMs are promising targets for inhibiting cancer. Anti-PD-1/PD-L1 immunotherapies have been used for an inhibition of PD-1/PD-L1 mediated T cell exhaustion in various cancers such as lymphoma, melanoma, and renal cancer with remarkable clinical success, however, most breast cancer patients have been reported to show resistances or short response durations. A lot of researches have been reported that targeting TAMs from tumor microenvironment synergized the effect of PD-1/PD-L1 therapies, suggesting that TAMs are major causes of PD-1/PD-L1 resistance. Previously, I have developed MEL-dKLA, a hybrid peptide that was conjugated with melittin (MEL) and pro-apoptotic peptide dKLA to eliminate M2 like TAM. In this study, I investigated whether removal of M2-like TAMs by MEL-dKLA enhanced the anti-cancer effect of PD-L1 antibodies in 4T1 breast cancer. Combination therapy with MEL-dKLA and anti PD-L1 delays tumor growth and increases survival. It inhibits the exhausted CD8+ T cell population in tumors, enabling them to perform cytotoxic functions. Simultaneous treatment with MEL-dKLA and anti PD-L1 reduced the contact area between TAM and CD8+ T cells in the tumor microenvironment. Therefore, these results suggested that MEL-dKLA and anti PD-L1 combination therapy will be promising for breast cancer treatments.
Targeting AXL-JAK1 in tumor and immune ecosystem of lung cancer
Authors: Taverna Josephine Amalia , Hung Chia-Nung , Dearmond Daniel , Chen Meizhen , Lin Chun-Lin , Osmulski Pawel , Gaczynska Maria , Wang Chiou-Miin , Lucio Nicholas Daniel , Chou Chih-Wei , Chen Chun-Liang , Bearss David , Warner Steve , Whatcott Clifford , Mouritsen Lars , Wade Mark , Weitman Steven , Mesa Ruben , Kirma Nameer , Huang Tim 
Published: January 2023

Abstract
Intercellular crosstalk between lung adenocarcinoma cells (LACs) and tumor-associated macrophages (TAMs) has been implicated in promoting cancer metastasis; however, how oncogenic signaling networks corroborate in this tumorigenic process remains unexplored. Our findings suggest that coordinated activation of AXL and JAK1-pSTAT3 signaling engenders a vicious cycle of dependence between LACs and TAMs for tumor progression. AXL-overexpressing LACs polarize TAMs to an M2-like phenotype in a JAK1-STAT3-dependent manner, facilitating the development of a proinflammatory tumor microenvironment. Conversely, M2-like TAMs release Gas6 ligand to enhance AXL-mediated cancer stemness and epithelial-to-mesenchymal transition (EMT) in LACs. Cytometry by time-of-flight (CyTOF) is a single-cell detection technology that allows for measurement of multiple protein markers in diverse cell subpopulations. We designed a 34-antibody CyTOF panel to identify immune cells, stromal cells, epithelial cells, oncogenic signaling, stemness and EMT components for LAC tumor profiling. CyTOF profiling of ~642,241 single cells detected 55 subpopulations among LAC cell lines (n=4 with co-culture conditions) and lung tumors (n=12), which were further differentiated based on their cell types (LACs, TAMs, stromal cells, granulocytes, natural killer, B and T lymphocytes). High AXL expression was noticed in tumor cell subpopulation while high pSTAT3 expression was detected in the TAM subpopulation. Moreover, pSTAT3 expression levels were increased in U937 differentiated macrophage after co-culture with A549 cells. This novel platform may facilitate the optimal selection of lung cancer patients for dual targeting of AXL and JAK1-pSTAT3.
LncRNA AK036396/FcnB regulating polymorphonuclear myeloid-derived suppressor cells in tumor bearing mice
Authors: Wang Shengjun , Tian Xinyu , Wang Tingting , Yin Kai , Zhu Dongwei , Ma Jie , Xu Huaxi 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs), which are constituted of immature myeloid cells, represent a population of heterogeneous cells derived from bone marrow. Activated and expanded MDSCs suppress the antitumor immune response by directly inhibiting T cell by high levels of Arg1, reactive oxygen species, and inducible nitric oxide synthase. Long non-coding RNAs (lncRNAs) are transcripts with lengths &gt;200 nts and without the capacity to encode proteins. With the development of RNA sequencing, lncRNAs that were previously considered “transcriptional noise” have been confirmed to be involved in regulating cellular biology. However, the role of lncRNAs in the development and function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) remains unclear. Here, we identified that the lncRNA AK036396 was highly expressed in PMN-MDSCs, and lncRNA AK036396 knockdown promoted the maturation and decreased the suppressive function of PMN-MDSCs. Ficolin B (Fcnb), whose expression could be used to reflect PMN-MDSC development, was the predicted target gene of lncRNA AK036396 based on microarray results. LncRNA AK036396 knockdown attenuated Fcnb protein stability in a manner dependent on the ubiquitin-proteasome system. Moreover, Fcnb inhibition downregulated the suppressive function of PMN-MDSCs. In addition, the expression of human M-ficolin, which is an orthologue of mouse Fcnb, was increased and positively correlated with arginase1 (Arg1) level in lung cancer patients. Based on these findings, lncRNA AK036396 can inhibit maturation and accelerate immunosuppression of PMN-MDSCs by enhancing Fcnb protein stability, which will be helpful for developing antitumor therapies targeting PMN-MDSCs.
IRF4 overexpression in therapeutic anti-tumor CD8 T cells inhibits tumor growth by driving functional state transition of therapeutic and endogenous CD8 T cells in tumors
Authors: yan hui , Zhang Hedong , Zou Dawei , Fu Jinfei , Zhang Xiaolong , Xiao Xiang , Guo Yang , Wang Guohua , Yu Anze , Li Xian C. , Chen Wenhao 
Published: January 2023

Abstract

Objective
We discovered that IRF4 inhibits CD4 T cell dysfunction after transplantation (Immunity 47:1114). Here we study the role of IRF4 in regulating anti-tumor CD8 T cell response.

Methods
In model 1, different tumor cell lines were injected s.c. into mice with T cell-specific IRF4 deletion or control mice. In model 2, B16F10 melanoma-reactive Pmel-1 CD8 T cells were transduced with IRF4-GFP or GFP-control, and injected i.v. into congenic mice at 3 days post-s.c. injection of B16F10 cells. On day 14, T cell states in tumors were defined by single cell RNA-seq and flow cytometric analyses.

Results
IRF4 deletion in T cells significantly accelerated the progression of syngeneic TRAMP-C1 prostate cancer and B16F10 melanoma, and even enabled the growth of allogeneic CT26 Balb/c tumors. Adoptive transfer of IRF4-GFP transduced Pmel-1 T cells was significantly more potent than GFP-control transuded Pmel-1 cells in inhibiting B16F10 melanoma growth. In the GFP-control cell-transfer group, most Pmel-1 and endogenous CD8 T cells in tumors remained naïve-like or transitory states (expressed TCF1 but not effector molecules). In the IRF4-GFP cell-transfer group, more than half of Pmel-1 and endogenous CD8 T cells in tumors successfully developed into effector T cells that expressed multiple effector molecules.

Conclusions
IRF4 in T cells governs anti-tumor immunity. IRF4 overexpression in therapeutic T cells improves their anti-tumor potency.
Blockade of CD80 interaction with PD-L1 between T and tumor cells augments effector T expansion and tumor immunity in a PD-1-dependent manner
Authors: ZHANG YUANKUN , Cassady Kaniel , Lee Michael , Nasri Ubaydah , Riggs Arthur D. , Feng Ru , Zeng Defu 
Published: January 2023

Abstract
PD-L1 interactions with PD-1 and CD80 play a critical role in regulating tumor immunity. Blockade of PD-L1 interaction with PD-1 between tumor and T cells augments tumor immunity. Cis-PD-L1/CD80 interactions reduce PD-L1 interaction with PD-1 on T cells and augment tumor immunity. However, whether trans-PD-L1 interaction with CD80 between tumor and T cells play a role in regulating tumor immunity remains unknown. In the current studies, using B16 and MC38 tumor lines in C57BL/6 mice with or without PD-1 or PD-L1 deficiency, we show that administration of anti-PD-L1 (43H12), a monoclonal antibody that specifically blocks PD-L1 interaction with CD80, augments tumor immunity. The effect is tumor PD-L1 interaction with PD-1 on T cells-dependent, because although 43H12 blockade does not augment tumor immunity in PD-1−/− mice or in PD-L1−/− mice with PD-L1 KO tumor lines, 43H12 blockade does augment tumor immunity in PD-L1−/− mice with wild-type tumor lines. Furthermore, consistent with CD28 requirement for augmenting anti-tumor immunity during blocking anti-PD-1 treatment, 43H12 blockade of PD-L1/CD80 interaction does not augment tumor immunity in CD28−/− mice. Finally, 43H12 blockade augments CD8+ T effector expansion in the tumor draining lymph nodes, with increased production of IFN-g and down-regulation of ps21-EZH2. These results indicate that blockade of PD-L1 interaction with CD80 can augment tumor immunity via down-regulating the effect of PD-L1 interaction with PD-1. (This work is supported by DMRI institutional funds and NIH 1R01CA228465-01 to Zeng).
DNA Hypomethylation of PDCD1 Gene in Korean Colorectal Cancer Patients
Authors: Lee YeongUn , Lee Ji-Yeon , Dho So-Hee , Cho Min-Jeong , Kim Jeong-Min , Kim Lark-Kyun 
Published: January 2023

Abstract
Colorectal cancer (CRC) is one of the most common and critical cancers, hence considerable effort has been focused on the identification of prognostic, diagnostic markers and therapeutic targets for CRC. Meanwhile, CRC is extensively known to be related to DNA methylation.
PD-1, also known as CD279, is a cell surface protein encoded by PDCD1 gene which acts as the immune checkpoint to terminate pro-inflammatory response of T cells at the right time. Recently, PD-1 has been reported to be aberrantly overexpressed in multiple cancers, hampering the anti-tumor function of T cells. Monoclonal antibodies (mAb) which target PD-1 have been used as cancer therapy, but there has been limited success with the use of immune checkpoint inhibitors.
We investigated the DNA methylation status of normal and tumor tissues of Korean CRC patients by performing the targeted bisulfite sequencing and identified that the promoter CpG island of PDCD1 is significantly hypomethylated in CRC tissue compared to its paired adjacent normal tissue. We have hypothesized the hypomethylation of promoter CpG island of PDCD1 is associated with aberrant expression of PD-1 and promotes immune evasion, eventually, development of CRC. Additionally, we are currently checking the possibility that hypomethylation of promoter CpG island of PDCD1 hinders the therapeutic effects of PD-1 monoclonal antibodies in CRC patients.
Detailing the mechanism of CDK5-mediated PD-L1 regulation in Medulloblastoma
Authors: abiff muta , Kingsley Daniel , Rauhe Peter , Benson Bryan , Petrosiute Agne , Huang Alex Yee-Chen 
Published: January 2023

Abstract
Novel therapies for the pediatric brain tumor medulloblastoma (MB) are hindered by limited knowledge of the roles played by host-derived cells at the local tumor site. Immune resistance in a murine model of MB (MM1) is associated with enhanced tumor expression of programmed death ligand-1 (PD-L1) in response to anti-tumor cytokine interferon-gamma (IFNγ) signaling. Disrupting this pathway via knockdown of cyclin dependent kinase 5 (CDK5), an essential transducer of the IFNγ signal, leads to an inflammatory tumor microenvironment (TME) and enhanced tumor rejection in vivo. In this study, we sought to detail the mechanism of CDK5-mediated PD-L1 regulation.
In response to IFNγ, PD-L1 expression is thought to be regulated at the promoter level by competition between the transcriptional activator IRF1 and repressor IRF2. We hypothesized that CDK5-IFNγ signaling inhibits IRF2 activity, resulting in unleashed PD-L1 promoter activity. We assessed IRF1/IRF2-DNA interactions using chromatin immunoprecipitation (ChIP) and gene reporter assays, with complementary analysis of PD-L1 transcription and surface expression with IRF1/IRF2 depletion.
ChIP-qPCR revealed a similar, IFNγ-induced enrichment of both IRF1 and IRF2 at the PD-L1 promoter. This is a surprising result, given the assumption that they compete for the same binding site and exert opposing effects. Additionally, inducible PD-L1 promoter activity was found to be decreased in tumors with IRF2 depletion. Together, these results suggest that IRF2 may be necessary for full activity of the PD-L1 promoter in MB. IRF1/IRF2 also bind to other cis-regulatory sites at genes that contribute to tumor immunogenicity, necessitating genome-wide characterization of their interactions.
Targeting TNFR2 to overcome acquired adaptive resistance to immune checkpoint blockade
Authors: Mayer Lena Sophie , Orlowski Robert J. , Giles Josephine , Benci Joseph L. , Ellis Gavin , Deng Guoping , Attanasio John , Chen Zeyu , Bengsch Bertram , Kahn Omar , Manne Sasikanth , Herati Ramin S. , Ngiow Shin , George Sangeeth M. , Faustman Denise L. , Gilliland Gary , Mick Rosemarie , Xu Wei , McGettigan Suzanne , Xu Xiaowei , Amaravadi Ravi K. , Karakousis Giorgos C. , Schuchter Lynn M. , Mitchell Tara C. , Riley James L. , Huang Alexander C. , Minn Andy , Tomov Vesselin , Wherry E. John 
Published: January 2023

Abstract
Overcoming acquired adaptive immune resistance to anti-PD-1 therapy is imperative for enhancing the efficacy of immune checkpoint blockade (ICB) in solid tumors. Regulatory T cells (Tregs) play a prominent role in the suppressive tumor microenvironment (TME) and are major contributors to adaptive immune resistance. Tregs limit CD8+ T cell reinvigoration and are a promising target for combination therapy. While the clinical efficacy of anti-CTLA4 may be partially explained by restriction of Tregs, its co-administration with anti-PD1 causes significant toxicity. Thus, safer approaches to limit Treg activity are needed. To elucidate the dynamic changes in immuno-regulatory circuits within the TME during ICB, we performed deep immune profiling of peripheral blood and tumors from patients with advanced melanoma prior to (n=7) and after 1 cycle of anti-PD-1 therapy with pembrolizumab (n=9). Tregs were abundant in the TME and retained their immunosuppressive phenotype and functionality following anti-PD-1. Epigenetic, transcriptomic, and proteomic analysis of Tregs after ICB identified tumor necrosis factor receptor 2 (TNFR2) signaling as a possible driver of CD8+ T cell suppression. TNFR2 was preferentially expressed by Tregs in the TME (mean 18.03 %, SD +/− 10.13 %) relative to CD8+ T cells (mean 0.64 %, SD +/− 0.82 %) and peripheral Tregs (mean 3.16 %, SD +/− 3.21 %), suggesting it might be a safe and effective target for combination therapy. Indeed, dual blockade of TNFR2 and PD-1 led to potent CD8+ T cell expansion in two mouse tumor models, and restored sensitivity to ICB in a resistant murine model of melanoma. Our data suggest that anti-TNFR2 might synergize with current ICB by countering the development of adaptive immune resistance.
Tumor-specific CD8 T cell activation in draining lymph nodes supports the anti-tumor CD8 T cell response
Authors: Prokhnevska Nataliya , Cardenas Maria , Jansen Caroline , Valanparambil Rajesh , Master Viraj , Sanda Martin , Kissick Haydn 
Published: January 2023

Abstract
CD8 T cells are a critical part of the immune response to tumors, with CD8 T cell infiltration predicting disease progression in many types of cancer. Recent work in CD8 T cell immunology described how CD8 T cells respond to chronic diseases, finding two subsets of CD8 T cells within tumors. One is a stem-like CD8 T cell and the other is a terminally differentiated CD8 T cell with cytotoxic capabilities. Determining how tumor-specific CD8 T cells activate and differentiate is critical to understanding why some tumors are highly infiltrated. To study how tumor-specific CD8 T cells are activated, I have made a prostate cancer model that expresses the viral LCMV glycoprotein (GP) which acts as a tumor-specific antigen. We have used this model to study tumor-specific CD8 T cell activation by adoptively transferring LCMV GP specific TCR transgenic P14 CD8 T cells into TRAMPC1-LCMV-GP bearing mice. We have found when tumor-specific CD8 T cells are activated in the tumor-draining lymph node they acquire an undifferentiated but activated program, upregulating CD44, PD1 but retaining high TCF1 and CD62L expression. These undifferentiated activated CD8 T cells do not acquire a typical effector program that is seen in an acute viral infection such as LCMV Armstrong, yet they are able to migrate to the tumor to establish the anti-tumor response. In conclusion, tumor-specific CD8 T cells do not acquire an effector program after activation and instead gain an undifferentiated activated phenotype. These data suggest that tumor-specific CD8 T cells are activated in the TDLN and differentiate to become the stem-like CD8 T cells within the tumor, establishing the anti-tumor CD8 response.
Effect of ontogeny and vaccination on plasma adenosine deaminase (ADA)-1 and -2 levels across the first week of human life
Authors: Smolen Kinga , Plotkin Alec , Pak Jensen , Odumade Oludare , Idoko Olubukola , Pettengill Matthew , Ozonoff Al , Kollmann Tobias , Kampmann Beate , Levy Ofer 
Published: January 2023

Abstract

Introduction
Adenosine is a purine metabolite that acts on its leukocyte receptors to inhibit inflammatory and Th1-polarizing cytokine production. Newborns exhibit lower plasma levels of adenosine deaminase (ADA), an enzyme that metabolizes extracellular adenosine, resulting in elevated plasma adenosine levels and a Th2/anti-inflammatory bias. Humans express two ADA isoforms: ADA1 and ADA2. Characterizing the impact of ontogeny and vaccination on levels of ADA1 and ADA2 may provide insight into mechanisms regulating early life immune development.

Methods
Newborns were recruited at the MRC Unit-Gambia and randomized to either Hepatitis B (HepB), BCG, or the combination of both vaccines. Plasma was collected at birth (day of life (DOL) 0) and at DOL 1, 3, or 7. Plasma levels of ADA1 and ADA2 were measured by a chromogenic assay. Log-transformed ADA concentrations were compared using ANOVA.

Results
In this interim analysis, we measured n = 51–53 participants per vaccine group per timepoint. ADA2 activity ex vivo in plasma derived from Gambian newborns increased by median fold changes of 1.6 (control), 1.6 (HepB), 1.5 (BCG), and 1.9 (HepB+BCG) over the first week of life. The changes in ADA2 for all groups were statistically significant over DOL 0. HepB and BCG immunizations were both associated with statistically significant 1.5-fold decrease in ADA1 across the first week of life.

Conclusions
Neonatal plasma ADA2 activity rises across the first week of life, suggestive of ontogeny-specific changes that promote Th2/anti-inflammatory immune status. Immunization at birth with HepB or BCG may be associated with lower ADA1 across the first week of life. ADA isoforms may be useful biomarkers of immune development and vaccine responses.