Modulation Of Immune Cells Research Articles

IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice.

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5 + NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5 + NOD mice by generating Il-10-deficient BDC2.5 + NOD mice (BDC2.5 + Il-10 -/- NOD mice). Our results showed that BDC2.5 + Il-10 -/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5 + NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5 + Il-10 -/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5 + NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5 + NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.

Combining nanomedicine and immune checkpoint therapy for cancer immunotherapy.

Cancer immunotherapy has emerged as a pillar of the cancer therapy armamentarium. Immune checkpoint therapy (ICT) is a mainstay of modern immunotherapy. Although ICT monotherapy has demonstrated remarkable clinical efficacy in some patients, the majority do not respond to treatment. In addition, many patients eventually develop resistance to ICT, disease recurrence, and toxicity from off-target effects. Combination therapy is a keystone strategy to overcome the limitations of monotherapy. With the integration of ICT and any therapy that induces tumor cell lysis and release of tumor-associated antigens (TAAs), ICT is expected to strengthen the coordinated innate and adaptive immune responses to TAA release and promote systemic, cellular antitumor immunity. Nanomedicine is well poised to facilitate combination ICT. Nanoparticles with delivery and/or immunomodulation capacities have been successfully combined with ICT in preclinical applications. Delivery nanoparticles protect and control the targeted release of their cargo. Inherently immunomodulatory nanoparticles can facilitate immunogenic cell death, modification of the tumor microenvironment, immune cell mimicry and modulation, and/or in situ vaccination. Nanoparticles are frequently multifunctional, combining multiple treatment strategies into a single platform with ICT. Nanomedicine and ICT combinations have great potential to yield novel, powerful treatments for patients with cancer. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Cell Fate Reprogramming in the Era of Cancer Immunotherapy.

Advances in understanding how cancer cells interact with the immune system allowed the development of immunotherapeutic strategies, harnessing patients’ immune system to fight cancer. Dendritic cell-based vaccines are being explored to reactivate anti-tumor adaptive immunity. Immune checkpoint inhibitors and chimeric antigen receptor T-cells (CAR T) were however the main approaches that catapulted the therapeutic success of immunotherapy. Despite their success across a broad range of human cancers, many challenges remain for basic understanding and clinical progress as only a minority of patients benefit from immunotherapy. In addition, cellular immunotherapies face important limitations imposed by the availability and quality of immune cells isolated from donors. Cell fate reprogramming is offering interesting alternatives to meet these challenges. Induced pluripotent stem cell (iPSC) technology not only enables studying immune cell specification but also serves as a platform for the differentiation of a myriad of clinically useful immune cells including T-cells, NK cells, or monocytes at scale. Moreover, the utilization of iPSCs allows introduction of genetic modifications and generation of T/NK cells with enhanced anti-tumor properties. Immune cells, such as macrophages and dendritic cells, can also be generated by direct cellular reprogramming employing lineage-specific master regulators bypassing the pluripotent stage. Thus, the cellular reprogramming toolbox is now providing the means to address the potential of patient-tailored immune cell types for cancer immunotherapy. In parallel, development of viral vectors for gene delivery has opened the door for in vivo reprogramming in regenerative medicine, an elegant strategy circumventing the current limitations of in vitro cell manipulation. An analogous paradigm has been recently developed in cancer immunotherapy by the generation of CAR T-cells in vivo. These new ideas on endogenous reprogramming, cross-fertilized from the fields of regenerative medicine and gene therapy, are opening exciting avenues for direct modulation of immune or tumor cells in situ, widening our strategies to remove cancer immunotherapy roadblocks. Here, we review current strategies for cancer immunotherapy, summarize technologies for generation of immune cells by cell fate reprogramming as well as highlight the future potential of inducing these unique cell identities in vivo, providing new and exciting tools for the fast-paced field of cancer immunotherapy.

Abstract 523: Modulation of immune suppressive cells by toll-like 7 agonist DSP-0509 which leads to potentiate anti-tumor activity of radiotherapy

Abstract Toll-like receptors (TLRs) are a family of pattern-recognition receptors that recognize pathogen-associated molecular patterns. TLR7 stimulation in pDCs (plasmacytoid dendritic cell) induces type I interferon, which results in innate immune activation. We previously showed that intravenously injectable DSP-0509 activated anti-tumor immunity in combination with immune checkpoint inhibitors. In this study, we present that DSP-0509 can enhance anti-tumor activity of radiation therapy (RT). RT is generally known to induce not only anti-tumor effector T cells through immunogenic cell death, but also cause immune suppression. We assessed the modulatory activity of DSP-0509 on immune suppressive cells. In CD8+ T cell suppression assay in which CD8+ T cells were cocultured with mMDSC (monocytic myeloid-derived suppressor cell, CD11b+Gr-1low), DSP-0509 restored the proliferation of CD8+ T cell suppressed by mMDSC. In Treg differentiation assay, in which Treg (CD4+CD25+Foxp3+) was differentiated from naïve CD4+ T cell in the presence of TGF-β, DSP-0509 suppressed the Treg differentiation. Treg function was assessed in coculture system, in which proliferation of CTV-labeled (CellTrace™ Violet) CD4+ T cell was suppressed by Treg. DSP-0509 restored the proliferation of CD4+ T cell. As a next step, to confirm a combination effect with RT, DSR-0509 (5 mg/kg, weekly) was administered with RT (5 Gy x 5 consecutive day). The combination administration extended the survival of CT26-bearing mice. The ratio of effector memory T cell (CD8+CD62L-CD127+) in CD8+ T cell was increased after administration of combination of DSP-0509 with RT. ELISpot assay using splenocytes collected from CT26-bearing mice after the administration of combination of DSP-0509 with RT was conducted. As a result, the number of IFNγ secreting cytotoxic T lymphocytes (CTLs) that responded to gp70 peptide was increased in combination of DSP-0509 with RT. When CT26 cells were re-challenged to the mice that completely rejected tumor after combination of DSP-0509 with RT, no tumor growth was observed in all mice. Anti-CD8 antibody treatment prior to re-challenge of CT26 cells cancelled this memory effect. qPCR analysis using mRNA isolated from treated tumor was conducted. RT monotherapy increased the expression of Cd8b1, but addition of DSP-0509 further enhanced the expression of Gzmb and Il12b in tumor. We showed two novel effects of DSP-0509 in this study, 1) modulation of immune suppressive cells and 2) extension of the survival of tumor-bearing mice in combination with RT, which would be explained by the additive CTL activation and memory T cell induction. Taken together, these results supported the hypothesis that combination of DSP-0509 with RT may enhance the anti-tumor immune activity by modulating CTL activity as well as immune suppressive cells. Citation Format: Yosuke Ota, Yasuhiro Nagai, Masashi Goto, Jun Oishi, Setsuko Yamamoto. Modulation of immune suppressive cells by toll-like 7 agonist DSP-0509 which leads to potentiate anti-tumor activity of radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 523.

Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

Tumor innervation: peripheral nerves take control of the tumor microenvironment.

In recent decades, cancer research has expanded exponentially beyond the study of abnormally dividing cells to include complex and extensive heterotypic interactions between cancer and noncancer cells that constitute the tumor microenvironment (TME). Modulation of stromal, immune, and endothelial cells by cancer cells promotes proliferation, survival, and metabolic changes that support tumor growth and metastasis. Recent evidence demonstrates that tumors can recruit peripheral nerves to the TME, leading to enhanced tumor growth in a range of cancer models through distinct mechanisms. This process, termed tumor innervation, is associated with an aggressive tumor phenotype and correlates with poor prognosis in clinical studies. Therefore, the peripheral nervous system may play an underrecognized role in cancer development, harboring targetable pathways that warrant investigation. To date, nerves have been implicated in driving proliferation, invasion, metastasis, and immune evasion through locally delivered neurotransmitters. However, emerging evidence suggests that cell-cell communication via exosomes induces tumor innervation, and thus exosomes may also mediate neural regulation of the TME. In this Review, seminal studies establishing tumor innervation are discussed, and known and putative signaling mechanisms between peripheral nerves and components of the TME are explored as a means to identify potential opportunities for therapeutic intervention.

D-enantiomers of CATH-2 enhance the response of macrophages against Streptococcus suis serotype 2

IntroductionDue to the increase of antibiotic resistant bacterial strains, there is an urgent need for development of alternatives to antibiotics. Cathelicidins can be such an alternative to antibiotics having both a direct antimicrobial capacity as well as an immunomodulatory function. Previously, the full d-enantiomer of chicken cathelicidin-2 (d-CATH-2) has shown to prophylactically protect chickens against infection 7 days post hatch when administered in ovo three days before hatch. ObjectivesTo further evaluate d-CATH-2 in mammals as a candidate for an alternative to antibiotics.In this study, the prophylactic capacity of d-CATH-2 and two truncated derivatives, d-C(1–21) and d-C(4–21), was determined in mammalian cells. MethodsAntibacterial assays; immune cell differentiation and modulation; cytotoxicity, isothermal titration calorimetry; in vivo prophylactic capacity of peptides in an S. suis infection model. Resultsd-CATH-2 and its derivatives were shown to have a strong direct antibacterial capacity against four different S. suis serotype 2 strains (P1/7, S735, D282, and OV625) in bacterial medium and even stronger in cell culture medium. In addition, d-CATH-2 and its derivatives ameliorated the efficiency of mouse bone marrow-derived macrophages (BMDM) and skewed mouse bone marrow-derived dendritic cells (BMDC) towards cells with a more macrophage-like phenotype. The peptides directly bind lipoteichoic acid (LTA) and inhibit LTA-induced activation of macrophages. In addition, S. suis killed by the peptide was unable to further activate mouse macrophages, which indicates that S. suis was eliminated by the previously reported silent killing mechanism. Administration of d-C(1–21) at 24 h or 7 days before infection resulted in a small prophylactic protection with reduced disease severity and reduced mortality of the treated mice. Conclusiond-enantiomers of CATH-2 show promise as anti-infectives against pathogenic S. suis for application in mammals.

Safety, pharmacokinetic and pharmacodynamic results from dose escalation of SAR439459, a TGFβ inhibitor, as monotherapy or in combination with cemiplimab in a phase 1/1b study.

2510 Background: SAR439459 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. In preclinical models, combining SAR439459 with an anti-PD-1 showed improved anti-tumor activity compared to single agent. Here we report preliminary results of SAR439459 ± cemiplimab in a first in human study. Methods: This is an open-label study (dose escalation and expansion) of SAR439459 ± cemiplimab administered intravenously in adult patients with advanced solid tumors to determine safety and tolerability, the maximum tolerated dose (MTD) and/or maximum administered dose (MAD) of SAR439459 ± cemiplimab, pharmacokinetics (PK); pharmacodynamic (PD) and preliminary clinical benefit. In Part 1A, SAR439459 (0.05-15 mg/kg) was administered as monotherapy Q2W in an adaptive Bayesian design with overdose control. In Part 1B, SAR439459 doses cleared from monotherapy were administered in combination with fixed dose of cemiplimab (3 mg/kg Q2W or 350 mg Q3W) in a 3+3 design. Results: As of 31 January 2020, 28 (1A) and 24 (1B) patients with ECOG performance status of 0-1 with a median age of 60.5 and 63 years respectively were enrolled. In Part 1A, 25 patients (89.3%) had at least one treatment emergent adverse event (TEAE) and 15 (53.5%) experienced grade (G)≥ 3 events. In Part 1B, 22 patients (91.7%) had at least one TEAE and 14 (58.3%) experienced G ≥ 3 events. Dose-limiting toxicities (DLTs) were evaluable in 24 and 21 patients respectively. In 1A, 2 DLTs were reported in 2 of 8 evaluable patients in dose level (DL) 4: G5 brain stem hemorrhage in a patient on concomitant low molecular weight heparin treatment and G3 myocardial infarction in a patient with diabetes, chronic kidney disease, chronic obstructive pulmonary disease, and hypertension. In 1B, 1 of 6 evaluable patients in DL5 had DLTs (G3 ALT and AST increase). MTD was not reached in either part. Ten patients had best overall response of stable disease: 6 in 1A and 4 in 1B. The PK of SAR439459 was dose proportional over the dose range tested with no evidence of cemiplimab effect on SAR439459 PK, when given in combination. Treatment with SAR439459 ± cemiplimab led to rapid reduction in total plasma TGFβ level in all dose levels tested and induced CD8 & NK cells expansion and Th1 cytokines production, suggesting peripheral T cell activation. Preliminary results from paired tumor biopsies collected from patients treated with SAR439459 ± cemiplimab in expansion showed trend of TGFβ signaling pathway inhibition and conversion from excluded to inflamed tumor-immune phenotype. Conclusions: SAR439459 ± cemiplimab showed an acceptable tolerability profile overall. MTD was not reached. Peripheral and tumor target engagement and modulation of key immune cells was observed in treated patients. Dose expansion cohorts are currently enrolling selected solid tumor patients. Funding: Sanofi. Clinical trial information: NCT03192345.

Local delivery of FTY720 induces neutrophil activation through chemokine signaling in an oronasal fistula model

PurposeCleft palate repair surgeries lack a regenerative reconstructive option and, in many cases, develop complications including oronasal fistula (ONF). Our group has developed a novel murine phenocopy of ONF to study the oral cavity wound healing program. Using this model, our team previously identified that delivery of FTY720 on a nanofiber scaffold had a unique immunomodulatory effect directing macrophages and monocytes into a pro-regenerative state during ONF healing. Here, the objective of this study was to determine the effects of local biomaterial-based FTY720 delivery in the ONF model on the early bulk gene expression and neutrophil phenotypic response within the regenerating tissue.MethodsUsing a mouse model of ONF formation, a palate defect was created and was treated with FTY720 nanofiber scaffolds or (blank) vehicle control nanofibers. At 1 and 3 days post-implantation, ONF oral mucosal tissue from the defect region was collected for RNA sequencing analysis or flow cytometry. For the RNA-seq expression profiling, intracellular pathways were assessed using the KEGG Pathway database and Gene Ontology (GO) Terms enrichment interactive graph. To assess the effects of FTY720 on different neutrophil subpopulations, flow cytometry data was analyzed using pseudotime analysis based on Spanning-tree Progression Analysis of Density-normalized Events (SPADE).ResultsRNA sequencing analysis of palate mucosa injured tissue identified 669 genes that were differentially expressed (DE) during the first 3 days of ONF wound healing after local delivery of FTY720, including multiple genes in the sphingolipid signaling pathway. Evaluation of the DE genes at the KEGG Pathway database also identified the inflammatory immune response pathways (chemokine signaling, cytokine-cytokine receptor interaction, and leukocyte transendothelial migration), and the Gene Ontology enrichment analysis identified neutrophil chemotaxis and migration terms. SPADE dendrograms of CD11b+Ly6G+ neutrophils at both day 1 and day 3 post-injury showed significantly distinct subpopulations of neutrophils in oral mucosal defect tissue from the FTY720 scaffold treatment group compared to the vehicle control group (blank). Increased expression of CD88 and Vav1, among other genes, were found and staining of the ONF area demonstrated increased VAV1 staining in FTY720‐treated healing oral mucosa.ConclusionTreatment of oral mucosal defects using FTY720 scaffolds is a promising new immunotherapy to improve healing outcomes and reducing ONF formation during cleft palate surgical repair. Local delivery of FTY720 nanofiber scaffolds during ONF healing significantly shifted early gene transcription associated with immune cell recruitment and modulation of the immune microenvironment results in distinct neutrophil subpopulations in the oral mucosal defect tissue that provides a critical shift toward pro-regenerative immune signaling.

Tumor-Associated Neutrophils Drive B-cell Recruitment and Their Differentiation to Plasma Cells.

A major mechanism through which neutrophils have been suggested to modulate tumor progression involves the interaction and subsequent modulation of other infiltrating immune cells. B cells have been found to infiltrate various cancer types and play a role in tumor immunity, offering new immunotherapy opportunities. Nevertheless, the specific impact of tumor-associated neutrophils (TAN) on B cells has largely been overlooked. In the current study, we aimed to characterize the role of TANs in the recruitment and modulation of B cells in the tumor microenvironment (TME). We showed that TANs actively participate in the recruitment of B cells to the TME and identified TNFα as the major cytokine mediating B-cell chemotaxis by TANs. The recruitment of CD45+B220+CD138- splenic B cells by TANs in vitro resulted in B-cell phenotypic modulation, with 68.6% ± 2.1% of the total migrated B cells displaying a CD45-B220+CD138+ phenotype, which is typical for plasma cells. This phenotype mirrored the large proportion (54.0% ± 6.1%) of CD45-B220+CD138+ intratumoral B cells (i.e., plasma cells) in Lewis lung carcinoma tumors. We next confirmed that the differentiation of CD45+B220+CD138- B cells to functionally active CD45-B220+CD138+ plasma cells required contact with TANs, was independent of T cells, and resulted in IgG production. We further identified membranal B-cell activating factor (BAFF) on TANs as a potential contact mechanism mediating B-cell differentiation, as blocking BAFF-receptor (BAFF-R) significantly reduced IgG production by 20%. Our study, therefore, demonstrates that TANs drive the recruitment and modulation of B cells into plasma cells in the TME, hence opening new avenues in the targeting of the immune system in cancer.

A Combination of Atorvastatin and Aspirin Enhances the Pro-Regenerative Interactions of Marrow Stromal Cells and Stroke-Derived Monocytes In Vitro.

Background and Purpose: Marrow stromal cells (MSCs) are being tested in clinical trials for stroke patients. MSCs appear to promote recovery through secretomes that promote modulation of immune cells, including myeloid phagocytes. Many stroke patients have comorbidities such as metabolic syndrome, hypertension, hypercholesterolemia, and diabetes for which they are prescribed medications that might affect the function of MSCs and monocytes (Mo) when they are administered in stroke patients. We studied the effects of the two most commonly prescribed stroke medications, statin and statin plus aspirin, on the secretomes of MSCs and their modulation of Mo derived from stroke patients. Methods: Human MSCs, Mo and their co-cultures were exposed to atorvastatin or atorvastatin plus aspirin followed by secretome analysis at 24 h. Monocytes were isolated from healthy controls as well as stroke patients with NIHSS ranging from 11 to 20. Secretome composition was measured using multiplex immunoassay. We used MTT assay to measure proliferation of monocytes. The mixed model was used to analyze experimental data. p-values less than 0.05 were considered significant. Results: Atorvastatin and aspirin combination increased the release of IL-1RA from stroke Mo. In MSCs, atorvastatin and aspirin combination reduced the release of pro-inflammatory cytokines such as IL-6, IL-8, MCP-1 and IFN-γ. Atorvastatin alone reduced the release of IL-6, IL-8 and MCP-1 from co-cultures of stroke monocytes and MSCs. Combination of atorvastatin and aspirin had additive effect on reducing the secretion of IL-6 from co-cultures of stroke Mo and MSCs. Conclusion: Atorvastatin, alone and in combination with aspirin can promote anti-inflammatory effect by modulating the secretome profile of Mo and MSCs. Our results suggest that stroke trials involving the use of intravenous MSCs should consider the effect of aspirin and atorvastatin, both of which are administered to the majority of hospitalized ischemic stroke patients.

Exosomal Non-coding RNAs-Mediated Crosstalk in the Tumor Microenvironment.

Exosomes are secreted by different types of cells in tumor microenvironment (TME) and participate in multiple biological processes of tumors. Non-coding RNAs (ncRNAs) enveloped in exosomes and released to the TME are shown to be involved in tumorigenesis and development, as well as act as important intracellular communication mediators. However, the understanding on the exact regulatory functions and substrates of exosomal RNA is still at an early stage. In this review, we provided an overview on recent studies on exosomes mediating the modulation of both tumor cells and immune cells, then summarized the exosomal ncRNAs [such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)] secreted by tumor cells and stromal cells that exhibited potential capabilities to regulate tumor cell growth, progression, metastasis, drug resistance, and immune response. Our review may hopefully inspire a deeper understanding on the ncRNAs’ function as useful biomarkers for the diagnosis, prognosis, and as novel targets therapy for cancer.

Cancer-Associated Adipocytes in Breast Cancer: Causes and Consequences.

Breast cancer progression is highly dependent on the heterotypic interaction between tumor cells and stromal cells of the tumor microenvironment. Cancer-associated adipocytes (CAAs) are emerging as breast cancer cell partners favoring proliferation, invasion, and metastasis. This article discussed the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation in order to appreciate the molecular pathways that have been described to drive adipocyte dedifferentiation. Moreover, recent studies on the mechanisms through which CAAs affect the progression of breast cancer were reviewed, including adipokine regulation, metabolic reprogramming, extracellular matrix remodeling, and immune cell modulation. An in-depth understanding of the complex vicious cycle between CAAs and breast cancer cells is crucial for designing novel strategies for new therapeutic interventions.

CD24 for Cardiovascular Researchers: A Key Molecule in Cardiac Immunology, Marker of Stem Cells and Target for Drug Development.

The study of the membrane protein, CD24, and its emerging role in major disease processes, has made a huge leap forward in the past two decades. It appears to have various key roles in oncogenesis, tumor progression and metastasis, stem cell maintenance and immune modulation. First described in the 1980s as the homologous human protein to the mouse HSA (Heat Stable Antigen), it was reported as a surface marker in developing hematopoietic cell lines. The later discovery of its overexpression in a large number of human neoplasms, lead cancer researchers to discover its various active roles in critical checkpoints during cancer development and progression. Targeting CD24 in directed drug development showed promising results in cancer treatment. More recently, the chimeric CD24-Fc protein has shown exciting results in clinical trials as a specific modulator of auto-inflammatory syndromes. This report is aimed to summarize the relevant literature on CD24 and tie it together with recent advancements in cardiovascular research. We hypothesize that CD24 is a promising focus of research in the understanding of cardiovascular disease processes and the development of novel biological therapies.

SHP2 Inhibition as a Promising Anti-cancer Therapy: Function in Tumor Cell Signaling and Immune Modulation

The protein tyrosine phosphatase SHP2, encoded by PTPN11, functions as a critical signal transduction regulator and interacts with key signaling molecules in both RAS/ERK and PD-1/PD-L1/ BTLA (B- and T-lymphocyte attenuator) pathways. Targeting SHP2 pharmacologically, therefore, may be a promising therapeutic strategy for many RAS-driven cancers.

MiRNAs and lncRNAs as Novel Therapeutic Targets to Improve Cancer Immunotherapy.

Simple SummaryCancer onset and progression are promoted by high deregulation of the immune system. Recently, major advances in molecular and clinical cancer immunology have been achieved, offering new agents for the treatment of common tumors, often with astonishing benefits in terms of prolonged survival and even cure. Unfortunately, most tumors are still resistant to current immune therapy approaches, and basic knowledge of the resistance mechanisms is eagerly awaited. We focused our attention on noncoding RNAs, a class of RNA that regulates many biological processes by targeting selectively crucial molecular pathways and that, recently, had their role in cancer cell immune escape and modulation of the tumor microenvironment identified, suggesting their function as promising immunotherapeutic targets. In this scenario, we point out that noncoding RNAs are progressively emerging as immunoregulators, and we depict the current information on the complex network involving the immune system and noncoding RNAs and the promising therapeutic options under investigation. Novel opportunities are emerging from noncoding-RNAs for the treatment of immune-refractory tumors.Immunotherapy is presently one of the most promising areas of investigation and development for the treatment of cancer. While immune checkpoint-blocking monoclonal antibodies and chimeric antigen receptor (CAR) T-cell-based therapy have recently provided in some cases valuable therapeutic options, the goal of cure has not yet been achieved for most malignancies and more efforts are urgently needed. Noncoding RNAs (ncRNA), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), regulate several biological processes via selective targeting of crucial molecular signaling pathways. Recently, the key roles of miRNA and lncRNAs as regulators of the immune-response in cancer have progressively emerged, since they may act (i) by shaping the intrinsic tumor cell and microenvironment (TME) properties; (ii) by regulating angiogenesis, immune-escape, epithelial-to-mesenchymal transition, invasion, and drug resistance; and (iii) by acting as potential biomarkers for prognostic assessment and prediction of response to immunotherapy. In this review, we provide an overview on the role of ncRNAs in modulating the immune response and the TME. We discuss the potential use of ncRNAs as potential biomarkers or as targets for development or clinical translation of new therapeutics. Finally, we discuss the potential combinatory approaches based on ncRNA targeting agents and tumor immune-checkpoint inhibitor antibodies or CAR-T for the experimental treatment of human cancer.

T helper 17 cells: A new actor on the stage of type2 diabetes and aging?

Metformin improves mitochondrial function and enhances autophagy of T helper 17 cells, leading to decreased inflammation. This highlights the importance of metabolic modulation of immune cells.

The Role of Cancer-Associated Fibroblasts in Tumor Progression.

Simple SummaryAs our knowledge of cancer as a complex organ comprising tumor cells as well as surrounding cells within the microenvironment continues to grow, it is imperative to consider how the microenvironment may be supporting the cancer and promoting tumor progression. One aspect of the microenvironment that has gained significant interest over the past decade are cancer-associated fibroblasts, which have been implicated in diverse oncogenic roles including cancer invasion and metastasis, resistance to existing cancer therapeutics, angiogenesis, and tumor proliferation. The identification of cancer-associated fibroblasts and the pathways through which they promote tumor progression will allow us to target a specific subset of cells within the cancer niche in order to augment existing cancer therapies and possibly develop novel methods. In this review, we discuss the different markers that have been used to identify cancer-associated fibroblasts in various cancer contexts as potential therapeutic targets and discuss the role that cancer-associated fibroblasts play in enhancing cancer malignancy.In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.

Comparative Analysis of Cytokine Expression in Oral Keratinocytes and THP-1 Macrophages in Response to the Most Prevalent Serotypes of Aggregatibacter actinomycetemcomitans.

Background: Periodontitis is a chronic inflammatory disease associated with a dysbiotic biofilm. Many pathogens have been related with its progression and severity, one of which is Aggregatibacter actinomycetemcomitans, a Gram-negative bacteria with seven serotypes (a–g) according with the structure of its LPS, with serotype b defined as the most virulent compared with the other serotypes. The aim of this study was to evaluate the response of oral keratinocytes and macrophages to A. actinomycetemcomitans. Methods: Oral keratinocytes (OKF6/TERT2) and macrophages (THP-1) were infected with A. actinomycetemcomitans serotypes a, b and c. The expression of IL-1β, IL-6, IL-8, IL-18, TNF-α, MMP-9, RANKL, TLR-2, TLR-4, TLR-6, thymic stromal lymphopoietin (TSLP), and ICAM-1 was evaluated by qPCR at 2 and 24 h after infection. Results: An increase in the expression of these molecules was induced by all serotypes at both times of infection, with macrophages showing higher levels of expression at 24 h compared to epithelial cells in which the highest levels were observed in the first hours after infection. Conclusions: Keratinocytes and macrophages contribute to the inflammation in periodontitis from the early stages of infection, producing the first waves of cytokines, acting as the first signal for professional immune cell recruitment and modulation of more specific immune responses.

Imaging of the glioma microenvironment by TSPO PET.

Gliomas are highly dynamic and heterogeneous tumours of the central nervous system (CNS). They constitute the most common neoplasm of the CNS and the second most common cause of death from intracranial disease after stroke. The advances in detailing the genetic profile of paediatric and adult gliomas along with the progress in MRI and PET multimodal molecular imaging technologies have greatly improved prognostic stratification of patients with glioma and informed on treatment decisions. Amino acid PET has already gained broad clinical application in the study of gliomas. PET imaging targeting the translocator protein(TSPO) has recently been applied to decipher the heterogeneity and dynamics of the tumour microenvironment (TME) and its various cellular components especially in view of targeted immune therapies with the goal to delineate pro- and anti-glioma immune cell modulation. The current review provides a comprehensive overview on the historical developments of TSPO PET for gliomas and summarizes the most relevant experimental and clinical data with regard to the assessment and quantification of various cellular components with the TME of gliomas by in vivo TSPO PET imaging.