bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of CD36 in macrophage lipid metabolism and function in tumor microenvironment
Authors: Xu Ziyan Zoe , Xu Shihao , Kuhlmann Alexandra , Kaech Susan M 
Published: January 2023

Abstract
Macrophages are a highly plastic population of innate immunity with diverse functions in homeostasis. Despite their relative abundance in tumor microenvironment (TME), the exact function of tumor-associated macrophages (TAMs) and how they are regulated remain largely unknown. Macrophages also play key roles in lipid metabolism, disruption of which can result in pathologies such as atherosclerosis. Interestingly, TME has also been characterized as a lipid-rich context, we are interested in understanding how lipids in TME affect TAMs’ pro- or anti-tumor function.
Here, we firstly characterized the lipid metabolic phenotype of TAMs in a mouse melanoma model. We found that up-regulation of lipid storage and uptake is associated with the most tolerogenic TAM subset marked by high level of F4/80. We also found high expression of scavenger receptor CD36 on F4/80hi TAMs which mediates uptake of oxidized LDL (oxLDL) from TME. Using germ line knockout (Cd36−/−) and myeloid-specific deficiency (Cd36 flox/flox x Csf1r-Cre) mouse models, we observed that uptake of oxLDL by TAMs was significantly blocked, along with rescued immunosuppressive phenotype characterized by decreased expression of PD-L1, CD206 and elevated secretion of TNFa, which together contribute to slower tumor growth. We further conducted single-cell RNA sequencing on Cd36−/− and wild-type TAMs, and found several pathways as potential mechanisms for CD36-mediated pro-tumor phenotype.
In conclusion, we discovered that high expression of CD36 on TAMs mediates uptake of oxLDL and contribute to pro-tumor function. Our data suggests that metabolites in TME may play crucial roles in metabolic and functional reprogramming of tumor-infiltrating immune populations.
BCG immunotherapy response associated immune transcriptomic and spatial immune profiles of non-muscle invasive bladder tumors
Authors: Chenard Stephen , Ren Runhan , Jackson Chelsea , Xu Amanda , Berman David , Siemens D. Robert , Koti Madhuri 
Published: January 2023

Abstract
Bladder cancer is a management-intensive disease that leads to ~200, 000 deaths worldwide every year. Upon initial diagnosis, approximately 75% of cases are categorized as non-muscle-invasive bladder cancer (NMIBC). Adjuvant Bacillus Calmette-Guérin (BCG) immunotherapy is the gold standard treatment for high risk NMIBC patients. Despite being used for over 40 years, many BCG patients exhibit tumor recurrence, a subset of which display progression to a muscle-invasive form of the disease that requires undesired bladder removal surgery.
We recently demonstrated that the interferon response induced by BCG could be further complemented via synergistic activation of the Stimulator of Interferon Genes (STING) pathway. Towards clinical translation of this combinatorial immunomodulation and in order to determine immune biomarkers associated with response to BCG, we retrospectively investigated the immune transcriptomic profiles of tumors from BCG responders and non-responders. Interestingly, tumors from BCG non-responders showed a higher immune cell abundance and higher immune checkpoint gene expression.
To further independently validate the transcriptomic findings at protein levels, we conducted spatial immune profiling of 12 immune cell markers (Ki-67+, CD8+ proliferating T cells, FoxP3+ T regulatory cells, CD79+ B cells, PD-1, PD-L1 and IDO1 immune checkpoints, CD68+ and CD163+ M1 and M2 macrophages) in a cohort of 571 NMIBC tumors. Preliminary findings showed that tumors from BCG non-responders are characterized by infiltration of immunosuppressive T regulatory cells. Findings from this study will have the potential to guide future immune biomarker guided immunomodulatory treatment combinations.
Intradermal delivery of a combination of immunomodulatory antibodies can promote rejection of hyperplastic skin in a mouse model of actinic keratosis
Authors: Wright Quentin , Minnie Simone , Leggatt Graham R 
Published: January 2023

Abstract
Effective immunotherapy strategies for cutaneous squamous cell carcinoma (SCC) and its precancerous lesion, actinic keratosis (AK), is an emerging area of interest in skin cancer research. Presently, clinical trials are focusing on systemic administration of immune checkpoint inhibitors and agonistic antibodies in advanced SCC. However, few studies have addressed the intradermal route of administration for antibody therapies, in either early stage SCC or AK.
In this study, we examined the effects of intradermal antibody therapy in combination with a topical TLR7/8 agonist, imiquimod, in a mouse model of precancerous skin. Using intradermal administration of anti-4-1BB and anti-PD-1 antibodies in combination with topical administration of imiquimod, precancerous skin grafted onto syngeneic recipients underwent a significant reduction in graft size relative to anti-PD-1/imiquimod and isotype antibody/sorbelene control cream groups. Interestingly, flow cytometry analysis of the anti-4-1bb/PD-1/ imiquimod and isotype/control cream groups, 14 days after cessation of therapy administration, revealed a distinct CD8 T cell subpopulation bearing hallmarks of T cell exhaustion (EOMES, PD-1, TIGIT and Tim-3 positive cells) in the spleen of the treatment group.
We conclude that intradermal and topical therapy combinations can induce favourable outcomes in the treatment of skin precancers.
T-cell Enriching Therapy using combination of IL-12 gene electrotransfer and anti-PD-1 attenuates the resistance of anti-PD1 in preclinical metastatic cancer
Authors: Shi Guilan , Scott Megan , Lundberg Cathryn , Heller Richard 
Published: January 2023

Abstract
Immune checkpoint blockades, such as anti-PD-1, have demonstrated significant clinical benefits. However, both primary and acquired resistance has become major obstacles. Limited immune cell infiltration into tumors and expression of PD-1 are two reasons leading to resistance to PD-1 inhibition. Our laboratory has demonstrated that expression of plasmid IL-12 delivered intraumorally can increase immune cell infiltration as well as potentially increase levels of PD-1. In this current study, we used the intraperitoneal metastatic B16F10 tumor model and report that IL-12 gene electrotransfer (IL-12 GET) combined with anti-PD-1 induced long-lived CD8+PD-1− T cells. Strikingly, the effector cytolytic activity of CTLs was expanded and maintained for up to 60 days, indicating that these cells do not differentiate into a memory functional phenotype. In vivo imaging results, illuminate a lower flux signal in B16.F10 intraperitoneal metastases following the combination treatment. Simultaneously, the primary subcutaneous tumors are fully regressed in most of these mice (80%). Expression of CD44+ CD62L− on CD8 CTLs increased with time, suggesting that the memory response was induced at around 120 days. Depletion experiments revealed that CD8+ T cells and CD4+ T cells were required for tumor regression. Our results revealed that this treatment not only boosted CD3+ T-cell infiltration into tumor mass but also upregulated the production of proinflammatory cytokines such as IFN-γ as well as chemokines CXCL9, CXCL10 and CXCL11, promoting accumulation of T cells to the tumor microenvironment and enhancing the effector functions of infiltrated T cells and simultaneously, attenuate the resistant of immune checkpoint blockade of anti-PD1.
Optimal Treatment Regimen of Using Chemo-Immunotherapy for Solid Tumors
Authors: Chaturvedi Pallavi , George Varghese , Liu Bai , Zhu Xiaoyun , Wang Meng , Rhode Peter , Wong Hing C 
Published: January 2023

Abstract
Chemotherapeutic agents not only cause apoptosis and necrosis of cancer cells but also induce cellular senescence (TIS), resulting in a persistent cell population that re-enters the cell cycle with stemness characteristics via the senescence-associated secretory phenotype. These senescent cancer cells, therefore, seed disease relapses if they are not effectively eliminated. TIS cancer cells lack HLA expression and cannot be targeted by T cells. Herein, we show that chemotherapy-induced senescent B16F10 cells express the NK ligands Rae1e and Ulbp1, and are effectively killed by mouse NK cells in vitro. Docetaxel treatment also induced senescent B16F10 cells in vivo. We have previously shown that the TGF-β trap/IL-15 fusion protein, aka HCW9218, effectively activates NK cells in vivo. Therefore, we treated B16F10 tumor bearing mice with docetaxel and then a single dose of HCW9218 in combination with the ADCC antibody TA99. This treatment regimen exhibited potent antitumor activity compared to docetaxel alone. End point analysis showed that HCW9218-treated tumors have lower mitotic activity, reduced expression of senescence markers, and increased frequencies of infiltrating CD8 T cells. We further showed in this model that HCW9218 treatment followed by anti-PD-L1 therapy was more effective than anti-PD-L1 therapy followed by HCW9218. These results suggest that the optimal sequence of cancer treatment is: (1) standard-of-care chemotherapy to control tumor burden and induce cellular senescence, (2) immunotherapy for removal of senescent cells and enhanced tumor infiltration of CD8+ T cells and (3) checkpoint blockade to maintain infiltrated T cell effector function to enhance therapeutic responses and treatment durability.
Glutamate receptor signaling is critical for T cell function and antitumor activity
Authors: Shanker Anil , de Aquino Maria Teresa Prudente , Hodo Thomas W , Uzhachenko Roman 
Published: January 2023

Abstract
The interaction between the nervous system and immune system has sparked interest in recent years. Emerging evidence shows an intricate neuroimmune network. We were intrigued by the expression of various neurotransmitter receptors on T lymphocytes. Specifically, following TCR stimulation, glutamate receptors (GluR) were significantly upregulated on both CD4+ and CD8+ T cells, with a peak at 48 h. Concomitant with the upregulation of activation molecules CD69, CD25 and CD44, proliferating CD8+ T cells presented higher levels of GluA3 and mGluR1 when compared with resting cells. By blocking group I metabotropic glutamate receptors and AMPA receptors through antagonists, we show that CD8+ T cells have a delayed activation but their viability is not altered. However, GluR blockade affected CD8+ T cell proliferation and their ability to kill tumor cells in vivo or target cells in vitro. While the frequency of GluR+CD8+ T cells ranges around 30% of total CD8+ T population, the effect of blocking glutamate signaling through receptor antagonists is a dominant effect and it is mediated by transient reduction in protein phosphorylation of TCR mediated pathways as well as calcium modulation. Overall, data suggest that glutamate receptors may have a stimulatory effect on T cell activation and glutamate agonists may boost T cell response in an immunosuppressive setting such as cancer.
Artemisinin improves the efficiency of anti-PD-L1 therapy in T-cell lymphoma
Authors: Yan Dehong , Zhang Mengqi , Adeshakin Adeleye O. , Wan Xiaochun 
Published: January 2023

Abstract
Although immune checkpoint inhibitors targeting PD-1/PD-L1 pathway have obtained favorable results in T-cell lymphoma clinical trials, the majority of T-cell lymphoma patients appear to be minimally sensitive to PD-1/PD-L1 blockade. The malaria drug artemisinin has previously been identified as a potent anti-lymphoma drug and was tested as a combination treatment with anti-PD-L1 antibody in T-cell lymphoma. In this study, we found that artemisinin caused ferroptosis by up-regulating ROS levels and increasing misfolded protein in T-cell lymphoma via down-regulating ERK pathway. As expected, artemisinin or anti-PD-L1 monoclonal antibody therapy alone could inhibit EL4 T-cell lymphoma growth in Balb/c nude mice. Interestingly, combination therapy with artemisinin greatly improved the anti-lymphoma efficiency of anti-PD-L1 monoclonal antibody. These results provide further rationale for the combination therapy of artemisinin with anti-PD-L1 antibody in preclinical settings.
This work was supported by the National Natural Science Foundation of China (Grant 81501356 and Grant 81373112), the Shenzhen Basic Science Research Project (Grants JCYJ20170413153158716 and JCYJ20170818164619194), Nanshan pilot team project (LHTD20160004), Start-up funding (CYZZ20180307154657923), Guangdong Provincial Research Award for Thousand Talents Program Scholars.
IL-37 suppresses hepatocellular carcinoma development through T cell activation and angiogenesis suppression
Authors: Zhu Ying , MEI YU , Liu Haiyan 
Published: January 2023

Abstract
IL-37, a relatively newly identified IL-1 family cytokine, has been shown to play an important immune regulatory role in inflammatory diseases, autoimmune diseases and carcinogenesis. IL-37 has been demonstrated to recruiting NK cells, stimulating CD4+ T cells, as well as inhibiting tumor angiogenesis to suppress tumor growth in various tumor models. In this current study, we found that IL-37 could suppress hepatocellular carcinoma (HCC) development in murine orthotopic HCC model and DEN-induced HCC model. Further study revealed that IL-37 could enhance the T cell killing capacity. This anti-tumor effect was fully abrogated in NOD-SCID mice. Furthermore, IL-37 could inhibit tumor angiogenesis in murine HCC model. In vitro study revealed that IL-37 treatment directly promoted HUVECs migration and tubule formation capacity, indicating IL-37 is a pro-angiogenic factor. However, the supernatant from IL-37 over-expression HCC cell line promoted HUVECs apoptosis and impaired the migration and tubule formation capacity of HUVECs. Microarray data suggested IL-37 affected the pro- and anti-angiogenic factors expression pattern from tumor cells. The pro-angiogenic factors ANGPT1, CYP1B1, FN1, MMP2, MCAM, PIK3CG were downregulated by IL-37, while the anti-angiogenic factor ANGPT1 was upregulated. These results indicated IL-37 could affect angiogenesis in both direct and indirect ways. Overall, our results demonstrated that IL-37 could suppress HCC development through T cell activation and angiogenesis suppression.
The role of the SWI/SNF complex in the tumor immune microenvironment
Authors: Chaudhri Apoorvi , Wang Yunfei , Shi Leilei , Singh Anand , Rai Kunal , Hwu Patrick 
Published: January 2023

Abstract
Remodeling of the chromatin is a regulatory mechanism in order to close or open the chromatin and mediate gene regulation. The SWI/SNF complex is evolutionary conserved and uses the energy from ATP to remodel the chromatin. This complex is mutated in about twenty percent of all human cancers. The subunits of the complex are known to have a tumor suppressor function, however this understanding can be debated. Studies have shown that in the event that one of the members is mutated, residual members of the complex can have aberrant activity more towards an oncogenic phenotype. The tumor suppressor or the oncogenic potential of this complex is context dependent and needs a deeper understanding. In the setting of a tumor, recent research has shown that, inhibition of the subunits of this complex can enhance the ability of the immune system to kill the tumor owing to their oncogenic potential. Here we discuss and analyze the various BAF, PBAF and the core catalytic subunits of the complex. Using both in-silico and wet lab approaches, we relate the functioning of the subunits to affect the tumor infiltrating immune cell subsets. Using data sets, we correlate the subunits with immune based therapy response. While each of the subunits play diverse roles, together we highlight the importance of this complex to shape the tumor immune landscape.
Formyl peptide receptor (FPR) agonists promote immune evasion independent of functional Ncf1 derived ROS
Authors: Bonner Michael Y. , Olofsson Peter , Holmdahl Rikard 
Published: January 2023

Abstract
Previous studies have shown that in both the absence of the Ncf1 gene or in the presence of a loss-of-function SNP, mice have a lower tumor burden when compared to wildtype animals. Here, we investigate a formyl peptide receptor (FPR) agonist in this setting and demonstrate that it promotes tumor immune evasion through an immune-Ncf1/ROS-dependent mechanism.
We observed an increased colonization of B16F10 tumor cells in the lungs of FPR-agonist-treated wildtype C57BL6N mice compared to vehicle-control-treated mice. A significant reduction in tumor burden was expectedly seen in the Ncf1*/* mutant strain compared to the wildtype. However, FPR-agonist treatment did not promote tumor growth in Ncf1*/* treated mice when compared to vehicle-control-treated Ncf1*/* mice. These results suggest that FPR agonists can promote tumor evasion by acting through FPRs on immune cells in a NOX2/ROS-independent fashion and in a fashion independent of FPRs on the tumor.
Host- versus cell-dependent effects of β-Arrestin 1 expression in prostate tumorigenesis
Authors: Adekoya Timothy Oluseyi , Smith Nikia , Richardson Micheler 
Published: January 2023

Abstract
Prostate cancer (PCa) constitutes a serious health challenge and remains one of the main causes of cancer-related death among men. The more aggressive form of the disease is androgen independent resulting in lack of response to androgen deprivation therapy. The scaffold proteins β-arrestin 1 and 2 (βarr1 and βarr2) which are known to mediate G protein-coupled receptors (GPCRs) desensitization and internalization, were also shown to modulate prostate tumorigenesis. βarr1 is overexpressed (~4 fold) in PCa cells relative to βarr2. In this study, we investigate the effect of β-arrestins expression in prostate tumorigenesis using in-vivo xenografts and autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) model deficient in β-arrestins expression. Depletion of βarr1 in TRAMP mice (TRAMP/βarr1−/−) increased PCa growth and decreased overall survival, relative to TRAMP and TRAMP/βarr2−/− animals. Tumors from TRAMP/βarr1−/− mice displayed increase androgen receptor (AR), but decrease prostate specific antigen (PSA) expression. In contrast, depletion of βarr1 in MDA PCa 2b cells (MDA PCa 2b-βarr1−/−) decreased cell proliferation, wound closure and anchorage independent cell growth compared to wild type MDA PCa 2b and MDA PCa 2b-βarr2−/− cells. Nude mice xenografts of MDA PCa 2b-βarr1−/− cells also showed significant decrease in tumor growth. Interestingly, tumor lysates from MDA PCa 2b-βarr1−/− xenografts exhibited decrease AR and increase PSA expression, relative to control tumors. Altogether, the data indicate that βarr1 modulates AR/PSA signaling to regulate prostate cancer aggressiveness. However, the effect of βarr1 is context-sensitive depending on its expression in the host relative to the tumor cells.
REPERTOIRE OF CIRCULATING ANTIBODIES CORRESPONDING TO MOLECULAR SUBTYPES OF BREAST CANCER
Authors: Chapoval Andrei I , Podlesnykh Stepan V , Kolosova Evgenia A , Shcherbakov Dmitry N , Shoikhet Jakov N , Lazarev Alexander F , Vikhlyanov Igor V , Sinkina Tatiyana V , Johnston Stephen A , Ilyichev Alexander A 
Published: January 2023

Abstract
Changes in the repertoire of circulating antibodies is a promising biomarker for various diseases. We have developed microarrays containing more than thousands of peptides with random amino acid sequences that can be used to analyze the entire repertoire of circulating antibodies. Using these peptide microarrays, we have shown that in the blood of patients diagnosed with breast cancer (BC) antibodies interacting with certain peptides are found. Moreover, circulating antibodies of patients with different molecular subtypes of BC (luminal A, luminal B and Basal-like) interact with different, but overlapping, panels of peptides. We have selected 634 peptides from 120K peptides presented on microarrays that specifically interact with circulating antibodies of blood plasma from patients with various subtypes of BC. This panel of peptides that specifically interact with the blood plasma immunoglobulins of patients with various molecular BC subtypes can be used for the development of non-invasive diagnostic test systems. Microchips containing thousands of peptides can be used as a tool for molecular screening populations at risk for various diseases. Thus, peptide microarrays can be used to create a new tool for studying the repertoire of circulating antibodies for different diseases evaluation, as well as for studying and evaluating protein-protein interactions.
Plasticity and Polarization of Human NK Cells in the Tumor Microenvironment
Authors: Moreno Nieves Uriel Y , Tay Joshua , Saumyaa Saumyaa , Mundy David , Sunwoo John B. 
Published: January 2023

Abstract
The presence and function of innate lymphoid cells (ILC), including natural killer (NK) cells, within human tumors has been poorly characterized. Here, we have assessed the heterogeneity of NK and ILC populations by single-cell RNA sequencing (scRNAseq) of hundreds of individual NK cells and ILCs within human head and neck squamous cell carcinoma (HNSCC), matched lymph node metastases, matched peripheral blood, and blood from healthy donors. Fresh tumor specimens and blood were obtained from 8 patients undergoing surgical resection of HNSCC. Unsupervised clustering revealed 8 different clusters of NK cells and ILC subsets. We observed significant heterogeneity, with distinct subsets showing profiles consistent with that of conventional NK cells, ILC1-like cells and ILC3-like cell. Importantly, peripheral NK cells were distinct from intratumoral NK cells. The presence of these different cell subsets within primary HNSCC tumors was confirmed by flow cytometry. Further, plasticity between the NK cell subsets was supported by in vitro and in vivo experimental data. Given the ability of NK and ILCs to polarize the immune responses through the secretion of cytokines and the ability of certain subsets to kill target cells, we hypothesize that the differences observed in NK and ILC populations and their plasticity may result in different immune responses, and may influence clinical outcomes following therapy.
Transcriptome network analysis identifies co-expressed CXCL13, CXCR5, and associated genes contributes to the aggressive phenotype of TNBC
Authors: Dill Courtney Denise , Dammer Eric , Griffen Tiara L , Young Corey D , Carey Kaylin , Nunez Sha’Kayla , Lillard James 
Published: January 2023

Abstract
Triple negative breast cancer (TNBC) is an aggressive disease associated with poor prognosis. Currently, there are no targeted therapies for this disease. Standard therapy for TNBC consists of a combination of chemotherapeutic drugs. However, patients often become resistant to this intervention and ultimately succumb to this disease. Hence, understanding the cellular and molecular mechanisms associated with TNBC progression is essential to develop more effective therapies. We hypothesize co-expressed CXCL13, CXCR5, and associated genes are significantly correlated with TNBC and poor overall survival. A bioinformatic approach was used to characterize this new potential drug target for TNBC. Our patient cohort was obtained from The Cancer Genome Atlas. Weighted gene network co-expression analysis identified gene networks associated with factors influencing BrCa prognosis. An ANOVA test identified genes differentially expressed among Luminal A, Luminal B, HER-2, and TNBC tumor groups. Finally, gene ontology analysis was performed via GO-ELITE and EPIC was used to estimate the proportion of various cell types found in bulk samples. We identified seven unique gene networks that were significantly and positively correlated with TNBC. The turquoise module (M1), contained CXCL13, CXCR5, and associated genes that drive tertiary lymphoid structure formation, regulation of immune response, and immune system processes. The M1 module was also significantly and positively correlated with TNBC, but not overall survival. The genes signatures contained in the M1 module were significantly correlated to CD8+ T cell, macrophage, B cell, CD4+ T cell, cancer-associated fibroblast, and NK cell, as determined by EPIC analysis.