bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased lymphatic circulation decreases CD4 counts in the lymph nodes of rats in adjuvant-induced arthritis
Authors: Swanson-Mungerson Michelle Anne , Magnuson Michael , Chang Min-Kyung , Hager Denver , Sperrazza Stephanie , Zanotti Brian , Incrocci Ryan , Volin Michael V 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is a disorder characterized by chronic inflammation. Rat adjuvant-induced arthritis (AIA) is a RA model with dysfunctional lymphatic circulation. We hypothesized that increasing lymphatic circulation would decrease arthritic inflammation. In order to determine if increasing lymphatic flow would decrease arthritic inflammation, we utilized osteopathic lymphatic manipulation (Lymphatic pump treatment (LPT)) during either the onset or during arthritis. LPT was performed by gradually increasing compression on the rat chest wall over 5 seconds followed by rapid release for 5 seconds. This technique was repeated for 1 minute 3X/day for 7 consecutive days either before the onset of inflammation (preventative treatment) or after measurable inflammation (therapeutic treatment). Articular index scoring, ankle caliper measurements, and peripheral blood, spleens, and popliteal lymph nodes were collected. In both the preventative and therapeutic studies, the LPT-treated rats had reduced inflammation. Therapeutically treated animals also had significantly decreased CD4+ lymphocytes in the draining popliteal lymph nodes, with increases in CD4+ cells in the spleen. These results suggest that LPT can reduce arthritis and alter lymphocyte trafficking in secondary lymphoid organs during inflammation. These data suggest that forced lymphatic circulation through osteopathic manipulation may serve to enhance current treatments to decrease inflammatory diseases.
Cancer stem cells inhibit NK cell effector function via PCNA-NKp44 interaction
Authors: Malaer Joseph D. , Mathew Porunelloor A 
Published: January 2023

Abstract
NK cells participate in the innate immune response against infection and cancer without prior sensitization. NK cell function depends on a balance of signals transmitted from activating and inhibitory receptors interacting with ligands on the surface of cells. Cancer cells may evade NK-mediated killing by expressing ligands for inhibitory receptors. Proliferating cell nuclear antigen (PCNA) associates with MHC I and forms the inhibitory ligand for NKp44, resulting in the inhibition of NK function. Cancer stem cells (CSC), a unique subset of tumor cells, possess a stem-cell-like phenotype and are thought to facilitate metastasis by escaping NK cell effector function. Pancreatic and colon CSC can be identified by co-expression of surface markers CD44 and CD133. In both cell lines, Panc-1 and HCT 116, cell surface PCNA is associated with co-expression of CD44 and CD133 as well as increased CSC transcription factor expression (NANOG, SOX2, and Oct-4). Blocking the interaction of NKp44 and PCNA enhanced the specific lysis of cells by NK cells. Collectively these data demonstrate that surface PCNA, CD44, and CD133 co-expression is a marker of pancreatic and colon CSC. Our research implicates that blocking NKp44-PCNA interaction may provide a novel immunotherapeutic target for pancreatic and colon cancer stem cells and prevent metastasis.
Pulsatile MEK inhibition improves anti-tumor immunity and T cell function in Kras mutant lung cancer
Authors: Choi Hyejin , Deng Jiehui , Li Shuai , Silk Tarik , Dong Lauren , Brea Eliott J , Redmond David C , Houghton Sean , Falik Nouraiz , Boiarsky Jonathan , Zhong Hong , Akbay Esra A , Smith Paul D , Merghoub Taha , Wong Kwok-Kin , Wolchok Jedd D 
Published: January 2023

Abstract
KRAS is one of the most commonly identified driver oncogene in non-small cell lung cancer (NSCLC) and is commonly associated with disease refractory to current available modalities of treatment. Targeted therapy to inhibit MEK has shown promising tumor growth control in preclinical models, but is followed by quick rebound of tumor growth. Recently, immune checkpoint blockade has shown clinical activity by dis-inhibiting T cells that are suppressed in the tumor microenvironment. We sought to identify the most effective therapy for the treatment of KRAS mutant NSCLC patients by targeting cancer cells and activating infiltrating immune cells concurrently. We focused on studying the impact of pulsatile MEK inhibition on the immune microenvironment. We found that pulsatile MEK inhibition maintained T cell activation better than continuous treatment ex vivo and in vivo. Treatment with two different MEK inhibitors (selumetinib and trametinib) each resulted in higher CTLA-4 and PD-1 expression in tumor-infiltrating T cells using pulsatile treatment, compared to continuous treatment in Kras mutant lung cancer mice. In addition, the pulsatile schedule showed a superior anti-tumor effect and delayed drug resistance compared to the continuous schedule. Further, combination of pulsatile MEK inhibitor treatment and CTLA-4 blockade resulted in the longest survival of Kras tumor-bearing mice. Similar experiments in immune deficient mice confirmed that this prolonged survival is conferred by adaptive immunity. Our findings set the foundation for a combinatorial therapeutic strategy using pulsatile targeted therapy together with immunotherapy in patients to optimally enhance tumor apoptosis and promote immune response simultaneously.
REAlease® Immunomagnetic Separation Technology with reversible labeling for tumor infiltrating T cells and sub-populations
Authors: Evaristo Cesar , Siemer Ramona , Agorku David , Brauner Janina , Hardt Olaf , Dose Christian , Richter Anne 
Published: January 2023

Abstract
Immunotherapies engaging T cells have proven clinical efficacy and tremendous potential. However, responses are often suboptimal. Further research is required to understand tumor-infiltrating leukocytes (TILs) biology and enhance outcomes. TIL analysis is technically challenging and labor intensive. Their number can be very low and small subpopulations may escape analysis as they get lost in the background noise. Importantly, tumor-infiltrating (TI) T cells are embedded in a highly immunomodulatory environment such that unbiased cell-intrinsic functional characterization is hindered. When working with large cohort sizes, even immunophenotyping TILs by flow cytometry is time consuming and data processing is laborious. Pre-enrichment of TI T cells is highly desirable to reduce hands-on time and generate high quality and reliable data.
We developed state-of-the-art CD4, CD8, CD3 and CD4/CD8 T cell specific enrichment reagents for magnetic cell sorting incorporating novel technology enabling the removal of both superparamagnetic beads and antibody fragments (REAlease®). Single cell suspension of human ovarian, pancreas or colon tumors was obtained by automated dissociation. TI T cell frequencies ranged from 0,5–14%, were isolated to high purities and with high yield. CD69 was not upregulated after 18h culture, and cells were functional for downstream applications. Importantly, REAlease technology allowed secondary magnetic isolation of sub-populations of T cells, such as gamma-delta T cells.
Our data demonstrates that magnetic enrichment using REAlease technology reduces time and increases quality of analysis, and is essential for the isolation of important T cell sub-populations within the tumor microenvironment.
Harnessing the anti-tumor activity of invariant natural killer T cells for neuroblastoma immunotherapy
Authors: Khurana Priya , Ferry Gabrielle , Karageorgos Spyridon , Vu Annette , McNerney Kevin , Hogarty Michael , Bassiri Hamid 
Published: January 2023

Abstract

Background
Invariant natural killer T (iNKT) cells are innate-like CD1d-restricted T cells that nucleate many anti-tumor immune pathways. In neuroblastoma (NB), a pediatric tumor of the sympathetic nervous system, intratumoral iNKT cell presence predicts better 5-year survival and prognosis. For optimal iNKT cell immunotherapy, an understanding of how they sustain effector function long-term within the tumor microenvironment (TME) is needed.

Results
Immunophenotyping of tumors from a mouse model of high-risk NB revealed a significant frequency of iNKT cells relative to conventional T cells (TCONV). To specifically redirect iNKT cell activity toward NB tumors, we developed a conjugate molecule (“CAb”) fusing a glycolipid antigen-loaded CD1d to an antibody directed against an NB-specific antigen. Acute CAb stimulation increased expression of cytokines and activation and degranulation markers specifically on intratumoral iNKT cells. Moreover, these expression levels were maintained upon chronic CAb stimulation. We postulate that iNKT cells can metabolically adapt to the nutrient-poor TME to withstand exhaustion. Transcriptional profiling of in vitro-stimulated iNKT cells and TCONV revealed differential expression patterns of genes in several metabolic pathways. We are now further defining the metabolic profile of iNKT cells and its link to anti-tumor function, and determining whether CAb activation of iNKT cells controls NB growth to improve survival.

Conclusions
iNKT cells within NB tumors can be activated and may possess unique metabolic and functional features from TCONV that confer sustained anti-tumor activity. Defining these properties will better inform the use of iNKT cells for solid tumor immunotherapy.
CD28 homolog is a strong activator of natural killer cells for lysis of B7H7-positive tumor cells
Authors: Zhuang Xiaoxuan , Long Eric O 
Published: January 2023

Abstract
The CD28–B7 family of receptor–ligand pairs regulate lymphocyte responses through costimulation and coinhibition. It includes checkpoint inhibitors, such as PD-1, which limit anti-tumor and anti-virus T cell responses. CD28 homolog (CD28H) and B7H7 have been identified as a new receptor–ligand pair in this family, which has costimulatory activity in T cells. Here we show that CD28H is expressed in primary natural killer (NK) cells and that it is a strong activator of NK cells through selective synergy with receptors NKp46 and 2B4 to induce degranulation, lysis of target cells, and production of pro-inflammatory cytokines. Expression of B7H7 on target cells enhanced both natural and antibody-dependent cellular cytotoxicity (ADCC) of NK cells. Mutation of tyrosine 192 on the CD28H cytoplasmic tail abolished NK cell activation through CD28H. As B7H7 is broadly expressed in tumor tissues, we engineered a CD28H chimeric antigen receptor (CD28H-CAR) consisting of full-length CD28H fused to the cytoplasmic domain of T cell receptor zeta chain. NK cell activation is controlled by dominant “self-inhibition” mediated by inhibitory receptors for MHC class I, which has been a constraint for NK cellular cancer therapy. Remarkably, expression of CD28H-CAR in NK cells triggered lysis of tumor cells expressing HLA-E and B7H7 by overriding inhibition mediated by the HLA-E receptor NKG2A. The cytoplasmic domains of both CD28H and TCR zeta chain were required for this activity. Thus, CD28H is a powerful activation receptor of NK cells that broadens their anti-tumor activity and holds promise as a component of NK-based CARs for cancer immunotherapy.
Monocyte-lineage dendritic cell (DC) precursors are pre-positioned in normal lymph nodes and rapidly differentiate into Batf3+ cross-presenting APCs during inflammation
Authors: Sharma Madhav D , Munn David H. 
Published: January 2023

Abstract
We have shown (Immunity 48:91–106, 2018) that a subset of murine monocytic precursor cells are plastic, and can up-regulate a Batf3-driven differentiation program resembling classical cDC1 cells. The resulting inflammatory DCs are important in tumor immunity, but it has been unclear whether they played a role in normal immune responses. We now identify the precursor cells for these inflammatory DCs as a population of Ly6c+ ckit+ c− fms+ CD11b-neg cells. These are constitutively present in all resting LNs (comprising up to half of the Ly6c+ cells). In response to a standard vaccination model of cross-presented antigen (whole OVA protein plus CpG adjuvant in IFA), the precursor cells rapidly up-regulated Batf3 and differentiated into CD103+ IRF8+ DCs. Just as in tumors, maturation was dependent on intracellular p53 signaling in the precursor cells. Targeted disruption of p53 (LysMcre/p53-KO) had no effect on the number of precursors, but abrogated their ability to mature into Batf3+ DCs. In KO mice, the loss of this single monocytic DC population entirely abrogated the ability to create an inflammatory milieu in the vaccine-draining LN, and abolished cross-presentation of protein antigen to T cells. In contrast, direct presentation (soluble siinfekl peptide) remained intact. We hypothesize that the ability of monocyte-lineage cells to differentiate into Batf3+ APCs during inflammation is an important component of the normal cross-presentation process.
Cannabinoids decrease intestinal permeability and induce colonic CD103+ dendritic cells to increase T regulatory cells leading to decreased murine colitis-associated colon cancer
Authors: Becker William J , Alrafas Haider , Nagarkatti Mitzi , Nagarkatti Prakash S 
Published: January 2023

Abstract
Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are two abundant phytocannabinoids found in Cannabis sativa. Cannabinoids bind to cannabinoid receptors 1 and 2 (CB1 and CB2), located primarily on the neurons and immune cells, respectively. Cannabis and synthetic THC and CBD are quickly gaining attention for their therapeutic potential in diseases ranging from epilepsy to multiple sclerosis, and cancer pain.
Colon cancer is the third leading cause of cancer-related deaths, and treatment options are limited to surgery, chemotherapy or radiation. Many physicians are now moving towards a strategy focused on prevention. Chronic inflammation is a cause of many cancers including colon cancer. Thus, we used a murine model of colitis induced colon cancer, wherein BL6 mice were given a single administration of carcinogen (azoxymethane) followed by DSS (1%) in the drinking water daily for 1 week followed by 2 weeks without DSS. This cycle, along with bi-weekly treatment with cannabinoids (CBD, THC, THC+CBD, or vehicle; all 10mg/kg; by oral gavage) continued for 10 weeks, as the progression of cancer was monitored.
Our data revealed that treatment with THC and THC+CBD resulted in decreased polyp formation in mice with colon cancer. We also showed that cannabinoids increased CD103+ dendritic cells in the colonic lamina propria that led to an increase in the CD4+Nrp1+FoxP3+ T regulatory cells (nTregs), which was dependent on CB2. Cannabinoids also increased the colonic barrier integrity as assessed by increased levels of ZO-1, through CB1, and increased mucus production. These changes collectively demonstrated cannabinoid treatment reduced the incidence of colitis-associated colon cancer by inducing an anti-inflammatory response.
A novel CSF-1R neutralizing antibody, DCB-AB21, inhibits colony stimulating factor 1 receptor signaling activity
Authors: Chen-Hsuan HO , Liao Chu-Bin , Chen Yu-Kai , Huang Chen-Wei , Yang Tze-Pin 
Published: January 2023

Abstract
Tumor-associated macrophages (TAMs) represent the major cell components of immune infiltrate in solid tumors, and it has been reported that high TAMs density is associated with poor clinical prognosis. Within the tumor microenvironment, TAMs rely on signaling through colony stimulating factor 1 receptor (CSF-1R)/CSF-1 axis for various tumor promoting processes such as tumor growth, angiogenesis, and metastasis. Therefore, decrease of TAMs density in tumors through CSF-1R inhibition is considered an attractive therapeutic target for drug development. In this study, we report that a novel anti-CSF-1R monoclonal antibody DCB-AB21 which specifically binds to CSF-1R and inhibits CSF-1R downstream signaling. Anti-proliferative activity was measured on murine Ba/F3 cells engineered to be dependent on CSF-1R, and our results showed DCB-AB21 can blocks the CSF-1 and IL-34-induced cell proliferation. Potent inhibition of CSF-1R-dependent signaling was observed in the Ba/F3 CSF-1R driven model cells, and in human THP-1 leukemia monocytic cell lines. Humanization engineering further improves this antibody’s affinity and anti-proliferative efficacy. The discovery of novel binding epitope of DCB-AB21 differentiates itself from the current CSF-1R targeting antibodies testing in clinical trials. In vivo efficacy of DCB-AB21 is now in progress.
Together, these data demonstrate that DCB-AB21 can potently inhibit CSF-1R in cellular contexts and that this activity has the potential to induce a phenotypic effect on macrophages. These data suggest that DCB-AB21 is a promising new agent with possibility to combine with immune checkpoint inhibitors to relief macrophage-dependent immune suppression and would yield clinical benefit.
MIF functional polymorphisms (−794 CATT5–8 and −173 G&gt;C) in Basal Cell Carcinoma in western Mexican population
Authors: Alvarado Emmanuel Valdés , Gutierrez Jorge Ramón Padilla , Valle Yeminia , González Mariana Pedroza , Martinez-Fernandez Diana Emilia , Valle Jose Francisco Muñoz , Guevera Elizabeth , Tlacuilo Alberto 
Published: January 2023

Abstract
Basal cell carcinoma (BCC) is the dermatological neoplasm more prevalent worldwide, in recent years there has been an increase in the number of cases becoming a health problem. Despite its high incidence, there is little information about genetic factors that lead to the carcinogenesis of this neoplasms. In the last years, macrophage migration inhibitory factor (MIF) has received particular attention, its expression has been linked to the development of different types of cancer. Therefore, the aim of this study was to investigate the genetic association of −794 CATT5–8 and −173 G&gt;C MIF polymorphisms with BCC.
A total of 150 BCC patients and 150 individuals with similar age than cases as a control group were recruited. Total genomic DNA was extracted from peripheral blood leukocytes by the salting out method. The −794 CATT5–8 MIF polymorphism was analyzed by conventional PCR and polyacrylamide gel electrophoresis, the −173 G&gt;C MIF polymorphism was genotyped by PCR-RFLP as was done in previous studies by our research group.
It was found that BCC incidence is higher in women than men additionally the localization of this neoplasia are more prevalent in head and neck. Also, it was found that the 5/5 genotype of the −794 CATT5–8 MIF polymorphisms of confers a risk to BCC development (OR=4.55, p=0.04). Respect to the −173 G&gt;C MIF polymorphism we did not find a statistical difference.
In conclusion, our findings suggest that the 5/5 genotyope of −794 CATT5–8 MIF polymorphism is associated with the development of BCC in patients from western Mexico. Further studies are needed due to the relation of the functions of MIF and de development of cancer.
Mesenchymal stem cells educate breast tumor associated macrophages to acquire increased immunosuppressive features
Authors: BISWAS SUBIR , Mandal Gunjan , Chowdhury Sougata Roy , Purohit Suman , Payne Kyle K. , Galindo Carmen Maria Anadon , Gupta Arnab , Yu Xiaoqing , Conejo-Garcia Jose R. , Bhattacharyya Arindam 
Published: January 2023

Abstract
Breast cancer metastasis is known to be extensively promoted by immunosuppression. Here we describe a novel mechanism by which mesenchymal stem cell (MSC)-derived exosomes drive an immunosuppressive program within the breast tumor microenvironment. Initial q-PCR and immunophenotyping of human breast tumor samples, and TCGA data analysis confirmed a positive correlation between infiltrations of MSC and M2 macrophage phenotype, therefore we hypothesized that MSC promote M2 macrophage differentiation in breast tumors. We then performed a series of experiments in vitro and in vivo, and found that MSC-derived exosomes significantly promote differentiation of macrophages into PD-L1 expressing ‘M2-like’ phenotype, while also enhancing malignant progression of breast tumors, in vivo. Additionally, we observed increased invasive potential of tumor cells with higher expression of mesenchymal markers when induced with MSC-derived exosomes. Importantly, our observation of a significantly higher TGF-β production by tumor associated macrophages in exosome-induced tumors, with stronger PD-1 expression by intra-tumoral T cells, suggests TGF-β driven PD-1 upregulation. Blocking of PD-L1 abrogates exosome-induced tumor growth signifying the PD-L1/PD-1 checkpoint pathway is vital to MSC-induced tumor progression. Together, infiltration of MSCs within breast tumors drives the increased invasive potential as well as immune-checkpoint-mediated immunosuppression through inducing PD-L1 expression by tumor associated macrophages and PD-1 expression by T cells. Targeting infiltration of MSCs into the breast tumor therefore is a potential approach to reduce breast tumor metastases and improve efficacy of immunotherapies.
IL-15 enhances anti-PD-1-induced reinvigoration of tumor-infiltrating CD8+ T cells
Authors: Leem Galam , Kim Kun Woo , Lee Jea-Ik , Ha Seung Yeon , Park Su-Hyung , Kang Shin Myung , Shin Eui-Cheol 
Published: January 2023

Abstract
IL-15 is a homeostatic cytokine that induces proliferation of NK cells and memory CD8+ T cells. Recently, clinical trials using various forms of IL-15 in combination with immune checkpoint inhibitors in multiple intractable cancers are on progress. In the present study, we examined effects of IL-15 on tumor-infiltrating CD8+ T cells obtained from human non-small cell lung cancer (NSCLC; n = 20) and synergic effects of IL-15 in combination with anti- PD-1 blocking antibodies. More than 80% of tumor-infiltrating CD8+ T cells expressed PD-1, indicating that they are exhausted. We stimulated tumor-infiltrating CD8+ T cells with anti-CD3 antibodies in the absence or presence of anti-PD-1 blocking antibodies and IL-15 and found that anti-PD-1 treatment increased anti-CD3-stimulated proliferation of tumor-infiltrating CD8+ T cells, indicating that tumor-infiltrating CD8+ T cells were reinvigorated by anti-PD-1. Moreover, IL-15 further enhances anti-PD-1-induced reinvigoration of tumor-infiltrating CD8+ T cells in a dose-dependent manner. These findings indicate that IL-15 might increase therapeutic effects of anti-PD-1 by synergistically enhancing anti-PD-1-induced reinvigoration of tumor-infiltrating CD8+ T cells.
Soluble FasL deficiency promotes CD8 T cell dependent elimination of primary intraocular tumors and liver metastases
Authors: McKenna Kyle C , McCullough Peter , Durbin Drew , O’Brien Grace , McDermott Meghan , Rothstein Ann Marshak 
Published: January 2023

Abstract
CD95/FasL is a membrane bound molecule that can be cleaved by metalloproteinases to produce a soluble form. The purpose of these experiments was to determine the influence of soluble CD95/FasL on intraocular tumor growth and liver metastases. P815 tumors transplanted into the anterior chamber of the eye of Balb/C J mice formed intraocular tumors that metastasized to the liver in 33% of mice. In contrast, ΔCS mice, engineered with a point mutation that prevents cleavage of membrane CD95/FasL to a soluble form, rejected intraocular tumors (ΔCS ocular tumor weight = 20+/− 15 mg; Balb/C J ocular tumor weight = 99+/−34) and did not develop liver metastases. Anti-tumor antibody responses were equivalent in Balb/C J and ΔCS mice with intraocular tumors. ΔCS mice depleted of CD8+ T Cells uniformly developed fatal liver metastases. These data indicate that soluble FasL normally inhibits tumor-specific CD8+ T cell responses to promote growth of primary intraocular tumors that metastasize to the liver.