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Biochemistry. Biokhimiia May 2024Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME) and the most abundant population of immune cells infiltrating a tumor.... (Review)
Review
Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME) and the most abundant population of immune cells infiltrating a tumor. TAMs can largely determine direction of anti-tumor immune response by promoting it or, conversely, contribute to formation of an immunosuppressive TME that allows tumors to evade immune control. Through interactions with tumor cells or other cells in the microenvironment and, as a result of action of anti-cancer therapy, macrophages can enter senescence. In this review, we have attempted to summarize information available in the literature on the role of senescent macrophages in tumors. With the recent development of senolytic therapeutic strategies aimed at removing senescent cells from an organism, it seems important to discuss functions of the senescent macrophages and potential role of the senolytic drugs in reprogramming TAMs to enhance anti-tumor immune response and improve efficacy of cancer treatment.
Topics: Tumor Microenvironment; Humans; Neoplasms; Tumor-Associated Macrophages; Cellular Senescence; Animals; Macrophages; Biomarkers, Tumor
PubMed: 38880645
DOI: 10.1134/S0006297924050055 -
Journal of Cranio-maxillo-facial... May 2024The aim of this study was to identify predictors of length of stay (LOS) after surgical therapy of maxillofacial abscess. Patients diagnosed with a maxillofacial abscess...
The aim of this study was to identify predictors of length of stay (LOS) after surgical therapy of maxillofacial abscess. Patients diagnosed with a maxillofacial abscess who underwent extraoral incision and drainage under general anesthesia between January 1st, 2012 and January 1st, 2022 were retrospectively reviewed Univariable and multivariable linear regressions were performed to identify the association between pre- and perioperative variables and the LOS. In total, 228 patients were included. In the forward stepwise multivariable analysis, all factors with a p-value <0.2 in the univariable model were included. Ultimately, six independent predictors of increased LOS were identified: female (coef. 0.14, 95% CI 0.03-0.25), immunosuppression (coef. 0.37, 95%CI 0.13-0.61), penicillin allergy (coef. 0.25, 95% CI 0.04-0.46), C-reactive protein (coef. 0.0008, 95% CI 0.0001-0.0014), multiple spaces involvement (coef. 0.36, 95% CI 0.13-0.59), and time to operation (coef. 0.005, 95% CI 0.002-0.008). In conclusion, our study provides new insights into predicting LOS for patients admitted with maxillofacial abscesses. The identification of these markers not only enhances the ability to forecast LOS, but also lays the groundwork for optimizing resource planning and potentially integrating them into a primary prevention algorithm.
PubMed: 38876956
DOI: 10.1016/j.jcms.2024.05.001 -
Immunobiology Jul 2024Recent evidence has shown that T cell exhaustion is implicated in Allergen-specific Immunotherapy (AIT). However, how T cell exhaustion plays a role in AIT is far from...
Recent evidence has shown that T cell exhaustion is implicated in Allergen-specific Immunotherapy (AIT). However, how T cell exhaustion plays a role in AIT is far from clear. Our study aimed to investigate T cell exhaustion associated with allergen exposure during AIT in mice. Ovalbumin (OVA) - sensitized C57BL/6J asthma mouse and AIT mouse models were constructed. Quantitative real-time PCR (qRTPCR) and flow cytometry were used to monitor the occurrence of local and systemic CD4 T cells and Th2T cells exhaustion in OVA-sensitized mice. The inhibitory surface marker programmed cell death protein 1 (PD-1) on CD4 T cells and Th2T cells was significantly upregulated in AIT mice compared with asthmatic and control mice. The level of PD-1 on the surface of CD4T cells of asthma mice was significantly higher than that of control mice. The inhibitory surface marker cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on CD4 T cells and Th2T cells showed no significant difference between the AIT, asthma and control mice. Collectively, our study indicated that the expression of PD-1 on CD4 T cells and Th2T cells was increased in AIT. Allergen exposure promotes the expression of PD-1 on the surface of CD4 T cells. T cell exhaustion plays an important role in AIT.
Topics: Animals; Programmed Cell Death 1 Receptor; Mice; CD4-Positive T-Lymphocytes; Asthma; Allergens; Desensitization, Immunologic; Th2 Cells; Mice, Inbred C57BL; Disease Models, Animal; Female; Biomarkers; Ovalbumin
PubMed: 38875763
DOI: 10.1016/j.imbio.2024.152824 -
Frontiers in Immunology 2024The five-year survival rates for pancreatic ductal adenocarcinoma (PDAC) have scarcely improved over the last half-century. It is inherently resistant to FDA-approved...
The five-year survival rates for pancreatic ductal adenocarcinoma (PDAC) have scarcely improved over the last half-century. It is inherently resistant to FDA-approved immunotherapies, which have transformed the outlook for patients with other advanced solid tumours. Accumulating evidence relates this resistance to its hallmark immunosuppressive milieu, which instils progressive dysfunction among tumour-infiltrating effector T cells. This milieu is established at the inception of neoplasia by immunosuppressive cellular populations, including regulatory T cells (T), which accumulate in parallel with the progression to malignant PDAC. Thus, the therapeutic manipulation of T has captured significant scientific and commercial attention, bolstered by the discovery that an abundance of tumour-infiltrating T correlates with a poor prognosis in PDAC patients. Herein, we propose a mechanism for the resistance of PDAC to anti-PD-1 and CTLA-4 immunotherapies and re-assess the rationale for pursuing T-targeted therapies in light of recent studies that profiled the immune landscape of patient-derived tumour samples. We evaluate strategies that are emerging to limit T-mediated immunosuppression for the treatment of PDAC, and signpost early-stage trials that provide preliminary evidence of clinical activity. In this context, we find a compelling argument for investment in the ongoing development of T-targeted immunotherapies for PDAC.
Topics: Animals; Humans; Carcinoma, Pancreatic Ductal; Immune Checkpoint Inhibitors; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Pancreatic Neoplasms; T-Lymphocytes, Regulatory; Tumor Microenvironment
PubMed: 38873607
DOI: 10.3389/fimmu.2024.1406250 -
Frontiers in Immunology 2024Autoimmune cytopenias (AICs) are a group of disorders characterized by immune-mediated destruction of blood cells. In children, they are often secondary to immune...
INTRODUCTION
Autoimmune cytopenias (AICs) are a group of disorders characterized by immune-mediated destruction of blood cells. In children, they are often secondary to immune dysregulation that may require long-lasting immunosuppression. Mycophenolate mofetil and sirolimus represent two well-tolerated options to treat these disorders, often as a steroid-sparing option. However, no data are available on the infection risk for patients undergoing long-lasting treatments.
PATIENTS AND METHODS
The rate of severe infective events was calculated in episodes per 100 persons/months at risk (p/m/r) documented by the analysis of hospitalization charts between January 2015 and July 2023 of patients treated with mycophenolate mofetil or sirolimus given for isolated AIC or AICs associated with autoimmune lymphoproliferative syndrome (ALPS)/ALPS-like syndromes in two large Italian pediatric hematology units.
RESULTS
From January 2015 to July 2023, 13 out of 96 patients treated with mycophenolate mofetil or sirolimus developed 16 severe infectious events requiring hospitalization. No patients died. Overall infection rate was 0.24 person/*100 months/risk (95% CI 0.09-0.3). Serious infectious events incidence was higher in patients with ALPS-like compared to others (0.42 versus 0.09; = 0.006) and lower in patients who underwent mycophenolate treatment alone compared to those who started sirolimus after mycophenolate failure (0.04 versus 0.29, = 0.03). Considering only patients who started treatment at the beginning of study period, overall cumulative hazard was 18.6% at 60 months (95% CI 3.4-31.4) with higher risk of infectious events after 5 years in ALPS-like patients (26.1%; 95% CI 3.2-43.5) compared to other AICs (4%; 95% CI 0-11.4; = 0.041).
DISCUSSION
To the best of our knowledge, this is the first study to describe the infectious risk related to mycophenolate and sirolimus chronic treatment in patients with AICs and immune dysregulation. Our data highlight that infection rate is very low and mainly related to the underlying hematological condition.
CONCLUSIONS
Mycophenolate and sirolimus represent a safe immunosuppressive therapy in AICs and immune dysregulation syndromes.
Topics: Humans; Mycophenolic Acid; Sirolimus; Female; Male; Child; Immunosuppressive Agents; Child, Preschool; Adolescent; Infant; Autoimmune Diseases; Infections; Risk Factors; Retrospective Studies; Incidence; Cytopenia
PubMed: 38873600
DOI: 10.3389/fimmu.2024.1415389 -
Stem Cell Research & Therapy Jun 2024Stem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with...
BACKGROUND
Stem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with instant blood-mediated inflammatory reactions, mechanical stress during administration, and replicative senescence or change in phenotype during long-term culture in vitro. In this study, we aimed to mobilize endogenous hematopoietic stem cells (HSCs) using AMD-3100 and provide local immune suppression using FK506, an immunosuppressive drug, for the treatment of inflammatory bowel diseases.
METHODS
Reactive oxygen species (ROS)-responsive FK506-loaded thioketal microspheres were prepared by emulsification solvent-evaporation method. Thioketal vehicle based FK506 microspheres and AMD3100 were co-administered into male C57BL6/J mice with dextran sulfate sodium (DSS) induced colitis. The effect of FK506-loaded thioketal microspheres in colitis mice were evaluated using disease severity index, myeloperoxidase activity, histology, flow cytometry, and gene expression by qRT-PCR.
RESULTS
The delivery of AMD-3100 enhanced mobilization of HSCs from the bone marrow into the inflamed colon of mice. Furthermore, targeted oral delivery of FK506 in an inflamed colon inhibited the immune activation in the colon. In the DSS-induced colitis mouse model, the combination of AMD-3100 and FK506-loaded thioketal microspheres ameliorated the disease, decreased immune cell infiltration and activation, and improved body weight, colon length, and epithelial healing process.
CONCLUSION
This study shows that the significant increase in the percentage of mobilized hematopoietic stem cells in the combination therapy of AMD and oral FK506 microspheres may contribute to a synergistic therapeutic effect. Thus, low-dose local delivery of FK506 combined with AMD3100 could be a promising alternative treatment for inflammatory bowel diseases.
Topics: Animals; Colitis; Mice; Benzylamines; Male; Cyclams; Dextran Sulfate; Mice, Inbred C57BL; Tacrolimus; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Hematopoietic Stem Cells; Disease Models, Animal; Immunosuppression Therapy; Immunosuppressive Agents; Microspheres; Reactive Oxygen Species
PubMed: 38872206
DOI: 10.1186/s13287-024-03777-2 -
Journal For Immunotherapy of Cancer Jun 2024The sustained effectiveness of anti-programmed cell death protein-1/programmed death-ligand 1 treatment is limited to a subgroup of patients with advanced nasopharyngeal...
BACKGROUND
The sustained effectiveness of anti-programmed cell death protein-1/programmed death-ligand 1 treatment is limited to a subgroup of patients with advanced nasopharyngeal carcinoma (NPC), and the specific biomarker determining the response to immunotherapy in NPC remains uncertain.
METHODS
We assessed the associations between pre-immunotherapy and post-immunotherapy serum lipoproteins and survival in a training cohort (N=160) and corroborated these findings in a validation cohort (N=100). Animal studies were performed to explore the underlying mechanisms. Additionally, the relationship between high-density lipoprotein-cholesterol (HDL-C) levels and M1/M2-like macrophages, as well as activated CD8+T cells in tumor tissues from patients with NPC who received immunotherapy, was investigated.
RESULTS
The lipoproteins cholesterol, HDL-C, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein A-1 (ApoA1), and apolipoprotein B, were significantly altered after immunotherapy. Patients with higher baseline HDL-C or ApoA1, or those with increased HDL-C or ApoA1 after immunotherapy had longer progression-free survival, a finding verified in the validation cohort (p<0.05). Multivariate analysis revealed that baseline HDL-C and elevated HDL-C post-immunotherapy were independent predictors of superior PFS (p<0.05). Furthermore, we discovered that L-4F, an ApoA1 mimetic, could inhibit tumor growth in NPC xenografts. This effect was associated with L-4F's ability to polarize M2-like macrophages towards an M1-like phenotype via the activation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65, thereby alleviating immunosuppression in the tumor microenvironment. Importantly, in patients with NPC with high plasma HDL-C levels, the number of M2-like macrophages was significantly decreased, while M1-like macrophages and activated CD8+T cells were notably increased in those with high HDL-C levels.
CONCLUSION
Higher baseline HDL-C levels or an increase in HDL-C post-immunotherapy can enhance immunotherapeutic responses in patients with NPC by reprogramming M2-like macrophages towards the M1 phenotype. This suggests a potential role for prospectively exploring ApoA1 mimetics as adjuvant agents in combination with immunotherapy.
Topics: Humans; Nasopharyngeal Carcinoma; Tumor-Associated Macrophages; Immunotherapy; Animals; Female; Male; Cholesterol, HDL; Mice; Middle Aged; Phenotype; Tumor Microenvironment; Nasopharyngeal Neoplasms; Adult
PubMed: 38871480
DOI: 10.1136/jitc-2023-008146 -
Revue Medicale de Liege Jun 2024Allergen immunotherapy is still the only curative treatment for respiratory allergies. It is based on repeated administration of allergenic extracts to sensitized... (Review)
Review
Allergen immunotherapy is still the only curative treatment for respiratory allergies. It is based on repeated administration of allergenic extracts to sensitized patients. It can be administered either by subcutaneous or by sublingual route. The purpose of the treatment is to modulate the immune response to a specific allergen and to alter the course of the disease over a long-term period. Numerous studies and meta-analyses have demonstrated its efficacy in terms of symptoms and quality of life improvement as well as reduction of the allergic march. Indication of allergen immunotherapy includes moderate to severe allergic rhinitis and mild to moderate allergic asthma from GINA step 3. Early intervention in sensitized patients is nowadays promoted.
Topics: Humans; Desensitization, Immunologic; Allergens; Asthma; Rhinitis, Allergic
PubMed: 38869131
DOI: No ID Found -
Frontiers in Immunology 2024Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and has a poor prognosis. Although immune checkpoint inhibitors have entered a new era... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and has a poor prognosis. Although immune checkpoint inhibitors have entered a new era of HCC treatment, their response rates are modest, which can be attributed to the immunosuppressive tumor microenvironment within HCC tumors. Accumulating evidence has shown that tumor growth is fueled by cancer stem cells (CSCs), which contribute to therapeutic resistance to the above treatments. Given that CSCs can regulate cellular and physical factors within the tumor niche by secreting various soluble factors in a paracrine manner, there have been increasing efforts toward understanding the roles of CSC-derived secretory factors in creating an immunosuppressive tumor microenvironment. In this review, we provide an update on how these secretory factors, including growth factors, cytokines, chemokines, and exosomes, contribute to the immunosuppressive TME, which leads to immune resistance. In addition, we present current therapeutic strategies targeting CSC-derived secretory factors and describe future perspectives. In summary, a better understanding of CSC biology in the TME provides a rational therapeutic basis for combination therapy with ICIs for effective HCC treatment.
Topics: Humans; Carcinoma, Hepatocellular; Tumor Microenvironment; Neoplastic Stem Cells; Liver Neoplasms; Animals; Exosomes; Cytokines; Intercellular Signaling Peptides and Proteins
PubMed: 38868769
DOI: 10.3389/fimmu.2024.1400112 -
Clinical Case Reports Jun 2024Concomitant native and prosthetic valve infective endocarditis (IE) is very rare, and both can rarely be complicated by rapidly progressive glomerulonephritis (RPGN)....
KEY CLINICAL MESSAGE
Concomitant native and prosthetic valve infective endocarditis (IE) is very rare, and both can rarely be complicated by rapidly progressive glomerulonephritis (RPGN). This diagnosis has therapeutic implications, as not all RPGN need immunosuppression therapy.
ABSTRACT
Native and prosthetic valve infective endocarditis (IE) may be rarely complicated by rapidly progressive glomerulonephritis (RPGN). The diagnosis of IE as a cause of RPGN may be missed, and patients may be subjected to inappropriate immune suppressive therapy. Moreover, IE involving multi-valves has rarely been described, and there are only few case reports of simultaneous native and prosthetic valve endocarditis. Here, we present a case of 34-year-old female patient who has RPGN and whose initial workup missed IE. However, further workup revealed a diagnosis of native and prosthetic valve IE and our patient, who would have been subjected to inappropriate immune suppressive therapy, was treated with intravenous antibiotics alone and discharged with improvement.
PubMed: 38868123
DOI: 10.1002/ccr3.9054