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Search Results (334)

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Keywords = myeloid-derived suppressor cell (MDSCs)

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16 pages, 5172 KiB  
Article
LAMP1 as a Target for PET Imaging in Adenocarcinoma Xenograft Models
by Bahar Ataeinia, Arvin Haj-Mirzaian, Lital Ben-Naim, Shadi A. Esfahani, Asier Marcos Vidal, Umar Mahmood and Pedram Heidari
Pharmaceuticals 2025, 18(8), 1122; https://doi.org/10.3390/ph18081122 - 27 Jul 2025
Viewed by 503
Abstract
Background: Lysosomal-associated membrane protein 1 (LAMP1), typically localized to the lysosomal membrane, is increasingly implicated as a marker of cancer aggressiveness and metastasis when expressed on the cell surface. This study aimed to develop a LAMP1-targeted antibody-based PET tracer and assess its efficacy [...] Read more.
Background: Lysosomal-associated membrane protein 1 (LAMP1), typically localized to the lysosomal membrane, is increasingly implicated as a marker of cancer aggressiveness and metastasis when expressed on the cell surface. This study aimed to develop a LAMP1-targeted antibody-based PET tracer and assess its efficacy in mouse models of human breast and colon adenocarcinoma. Methods: To determine the source of LAMP1 expression, we utilized human single-cell RNA sequencing and spatial transcriptomics, complemented by in-house flow cytometry on xenografted mouse models. Tissue microarrays of multiple epithelial cancers and normal tissue were stained for LAMP-1, and staining was quantified. An anti-LAMP1 monoclonal antibody was conjugated with desferrioxamine (DFO) and labeled with zirconium-89 (89Zr). Human triple-negative breast cancer (MDA-MB-231) and colon cancer (Caco-2) cell lines were implanted in nude mice. PET/CT imaging was conducted at 24, 72, and 168 h post-intravenous injection of 89Zr-DFO-anti-LAMP1 and 89Zr-DFO-IgG (negative control), followed by organ-specific biodistribution analyses at the final imaging time point. Results: Integrated single-cell and spatial RNA sequencing demonstrated that LAMP1 expression was localized to myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) in addition to the cancer cells. Tissue microarray showed significantly higher staining for LAMP-1 in tumor tissue compared to normal tissue (3986 ± 2635 vs. 1299 ± 1291, p < 0.001). Additionally, xenograft models showed a significantly higher contribution of cancer cells than the immune cells to cell surface LAMP1 expression. In vivo, PET imaging with 89Zr-DFO-anti-LAMP1 PET/CT revealed detectable tumor uptake as early as 24 h post-injection. The 89Zr-DFO-anti-LAMP1 tracer demonstrated significantly higher uptake than the control 89Zr-DFO-IgG in both models across all time points (MDA-MB-231 SUVmax at 168 h: 12.9 ± 5.7 vs. 4.4 ± 2.4, p = 0.003; Caco-2 SUVmax at 168 h: 8.53 ± 3.03 vs. 3.38 ± 1.25, p < 0.01). Conclusions: Imaging of cell surface LAMP-1 in breast and colon adenocarcinoma is feasible by immuno-PET. LAMP-1 imaging can be expanded to adenocarcinomas of other origins, such as prostate and pancreas. Full article
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27 pages, 1103 KiB  
Review
Tumor Microenvironmental Dynamics in Shaping Resistance to Therapeutic Interventions in Melanoma: A Narrative Review
by Laci M. Turner, Hanna Terhaar, Victoria Jiminez, Bailey J. Anderson, Emily Grant and Nabiha Yusuf
Pharmaceuticals 2025, 18(8), 1082; https://doi.org/10.3390/ph18081082 - 22 Jul 2025
Viewed by 440
Abstract
Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, [...] Read more.
Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed. Full article
(This article belongs to the Special Issue Combating Drug Resistance in Cancer)
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19 pages, 401 KiB  
Review
The Role of Protein Kinases in the Suppressive Phenotype of Myeloid-Derived Suppressor Cells
by Aikyn Kali, Nurshat Abdolla, Yuliya V. Perfilyeva, Yekaterina O. Ostapchuk and Raikhan Tleulieva
Int. J. Mol. Sci. 2025, 26(14), 6936; https://doi.org/10.3390/ijms26146936 - 19 Jul 2025
Viewed by 364
Abstract
Inflammation is a self-defense mechanism that controls the homeostasis of an organism, and its alteration by persistent noxious stimuli could lead to an imbalance in the regulation of inflammatory responses mediated by innate and adaptive immunity. During chronic inflammation, sustained exposure of myeloid [...] Read more.
Inflammation is a self-defense mechanism that controls the homeostasis of an organism, and its alteration by persistent noxious stimuli could lead to an imbalance in the regulation of inflammatory responses mediated by innate and adaptive immunity. During chronic inflammation, sustained exposure of myeloid cells to the various inflammatory signals derived from inflamed tissue could lead to the generation of myeloid cells with an immunosuppressive state, called myeloid-derived suppressor cells (MDSCs), which can exert protective or deleterious functions depending on the nature of signals and the specific inflammatory conditions created by different pathophysiological contexts. Initially identified in various tumor models and cancer patient samples, these cells have long been recognized as negative regulators of anti-tumor immunity. Consequently, researchers have focused on elucidating the molecular mechanisms underlying their potent immunosuppressive activity. As a key component of the signal transducing processes, protein kinases play a central role in regulating the signal transduction mechanisms of many cellular activities, including differentiation and immunosuppression. Over the past decade, at least a dozen kinases, including mechanistic target of rapamycin (mTOR), phosphoinositide 3-kinases (PI3Ks), TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases (TAM RTKs), mitogen-activated protein kinases (MAPKs), and others, have emerged as key contributors to the generation and differentiation of MDSCs. Here, we discuss the recent findings on these kinases that directly contribute to the immunosuppressive functions of MDSCs. Full article
(This article belongs to the Section Molecular Immunology)
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20 pages, 18100 KiB  
Article
Targeting p-FGFR1Y654 Enhances CD8+ T Cells Infiltration and Overcomes Immunotherapy Resistance in Esophageal Squamous Cell Carcinoma by Regulating the CXCL8–CXCR2 Axis
by Hong Luo, Liwei Wang, Hui Gao, Daijun Zhou, Yu Qiu, Lijia Yang, Jing Li, Dan Du, Xiaoli Huang, Yu Zhao, Zhongchun Qi, Yue Zhang, Xuemei Huang, Lihan Sun, Tao Xu and Dong Li
Biomedicines 2025, 13(7), 1667; https://doi.org/10.3390/biomedicines13071667 - 8 Jul 2025
Viewed by 496
Abstract
Background: Esophageal squamous cell carcinoma (ESCC) is a fatal malignant tumor. Several studies have demonstrated that immune checkpoint inhibitors can provide clinical benefits to patients with ESCC. However, the single-agent efficacy of these agents remains limited. Although combination therapies (e.g., radiotherapy, chemotherapy) can [...] Read more.
Background: Esophageal squamous cell carcinoma (ESCC) is a fatal malignant tumor. Several studies have demonstrated that immune checkpoint inhibitors can provide clinical benefits to patients with ESCC. However, the single-agent efficacy of these agents remains limited. Although combination therapies (e.g., radiotherapy, chemotherapy) can help to overcome immunotherapy resistance in ESCC, their severe side effects limit clinical application. This study aimed to explore new resistance mechanisms to immunotherapy in ESCC and identify novel molecular targets to overcome immunotherapy resistance. Methods: We employed immunohistochemistry staining to examine the p-FGFR1Y654 in tumor samples obtained from 103 patients with ESCC, in addition to evaluating CD8+ T cell infiltration. In vitro expression, western blotting, CCK-8, 5-bromo-2′-deoxyuridine incorporation assays, and migration assays were used to confirm the impact of AZD4547 on p-FGFR1Y654 expression and the proliferation and migration in ESCC cell lines. Through RNA sequencing analysis, databases such as the Cancer Genome Atlas (TCGA) and Gene Set Cancer Analysis (GSCA), and the reconstruction of transgenic mice using the humanized immune system, we validated the correlation between the expression of p-FGFR1Y654 and CD8+ T cell infiltration. We also explored how p-FGFR1Y654 recruits myeloid-derived suppressor cells (MDSCs) through the CXCL8–CXCR2 axis to suppress the therapeutic efficacy of immunotherapy in ESCC. Finally, the tumor-suppressive effects of AZD4547 combined with immunotherapy were confirmed in vivo in tumor-bearing mice with a humanized immune system. Results: We found that the inhibition of p-FGFR1Y654 expression in ESCC can enhance CD8+ T cell infiltration by suppressing the CXCL8-–XCR2 recruitment of MDSCs. AZD4547, combined with immunotherapy, further promotes immunotherapeutic efficacy in ESCC. Conclusions: In conclusion, our study presents a promising model for combination therapy in ESCC immunotherapy. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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15 pages, 758 KiB  
Review
Myeloid-Derived Suppressor Cells (MDSCs) at the Crossroad of Senescence and Cancer
by Giovanna Talarico, Stefania Orecchioni, Paolo Falvo and Francesco Bertolini
Cancers 2025, 17(13), 2251; https://doi.org/10.3390/cancers17132251 - 4 Jul 2025
Viewed by 477
Abstract
The family of myeloid-derived suppressor cells (MDSCs) includes a heterogeneous group of partially immature cells belonging to the myeloid lineage with potent immunosuppressive functions. They might be increased in the peripheral blood of cancer patients and in the microenvironment of cancer lesions, where [...] Read more.
The family of myeloid-derived suppressor cells (MDSCs) includes a heterogeneous group of partially immature cells belonging to the myeloid lineage with potent immunosuppressive functions. They might be increased in the peripheral blood of cancer patients and in the microenvironment of cancer lesions, where they act in suppressing adaptive and innate immune cells, promoting tumor progression, and facilitating resistance to therapy. Several—albeit still limited—studies have shown higher levels of MDSCs in elderly cancer patients, correlating with poorer outcomes and a reduced response to immunotherapies. Thus, MDSCs may serve as biomarkers for prognosis or therapy response in this population, and MDSC-targeting therapies aimed at reducing their number or function may enhance the effectiveness of immunotherapies in older adults. Additionally, a better understanding of MDSCs may help to overcome some age-related barriers in cancer treatments. Full article
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20 pages, 3541 KiB  
Review
Immunoregulation in Fungal Infections: A Review and Update on the Critical Role of Myeloid-Derived Suppressor Cells
by Valéria de Lima Kaminski, Ana Luiza Oliveira Menezes, Kauan Gonçalves de Lima, Stephani Leonelo de Almeida, Diego Vinícius Alves da Silva, Filipe Nogueira Franco, Nycolas Willian Preite and Flávio Vieira Loures
J. Fungi 2025, 11(7), 496; https://doi.org/10.3390/jof11070496 - 30 Jun 2025
Viewed by 550
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune cells that play a central role in regulating host immune responses during fungal infections. Their recruitment is mediated by pathogen recognition receptors, particularly Dectin-1 and CARD9 signaling, which promote the production of reactive [...] Read more.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune cells that play a central role in regulating host immune responses during fungal infections. Their recruitment is mediated by pathogen recognition receptors, particularly Dectin-1 and CARD9 signaling, which promote the production of reactive oxygen species (ROS) and IL-1β. Once activated, MDSCs suppress T-cell and natural killer cell functions through immunosuppressive cytokines like IL-10 and TGF-β, as well as enzymes such as arginase-1 and indoleamine 2,3-dioxygenase 1 (IDO-1). This review explores the role of MDSCs in fungal infections caused by Candida spp., Paracoccidioides brasiliensis, Aspergillus spp., and Cryptococcus neoformans, emphasizing their impact on immune modulation and disease progression. The emerging evidence suggests that fungal bioactive compounds, such as polysaccharides, can influence MDSC activity and restore immune balance. Notably, therapies targeting MDSCs have demonstrated promise in both fungal infections. In particular, infections with P. brasiliensis and C. neoformans show improved T-cell responses following MDSC-targeted interventions. Additionally, polysaccharides from Grifola frondosa and exposure to Aspergillus sydowii affect MDSC behavior, supporting the potential of modulating these cells therapeutically. Together, these findings highlight the relevance of MDSCs in fungal pathogenesis and underscore their potential as targets for immunotherapeutic strategies in infectious diseases. Full article
(This article belongs to the Special Issue Fungal Cell Biology)
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24 pages, 5289 KiB  
Article
Immunosuppressive Tumor Microenvironment of Osteosarcoma
by Aaron Michael Taylor, Jianting Sheng, Patrick Kwok Shing Ng, Jeffrey M. Harder, Parveen Kumar, Ju Young Ahn, Yuliang Cao, Alissa M. Dzis, Nathaniel L. Jillette, Andrew Goodspeed, Avery Bodlak, Qian Wu, Michael S. Isakoff, Joshy George, Jessica D. S. Grassmann, Diane Luo, William F. Flynn, Elise T. Courtois, Paul Robson, Masanori Hayashi, Alini Trujillo Paolillo, Antonio Sergio Petrilli, Silvia Regina Caminada de Toledo, Fabiola Sara Balarezo, Adam D. Lindsay, Bang Hoang, Stephen T. C. Wong and Ching C. Lauadd Show full author list remove Hide full author list
Cancers 2025, 17(13), 2117; https://doi.org/10.3390/cancers17132117 - 24 Jun 2025
Viewed by 1142
Abstract
Background/Objectives: Osteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective [...] Read more.
Background/Objectives: Osteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective therapies or improve outcomes over the last 40 years. Methods: To better understand the immune microenvironment of osteosarcoma, we performed single-cell RNA sequencing on six tumor biopsy samples, combined with a previously published cohort of six samples. Additional osteosarcoma samples were profiled using spatial transcriptomics for the validation of discovered subtypes and to add spatial context. Results: Analysis revealed immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory and exhausted T cells, and LAMP3+ dendritic cells. Conclusions: Using cell–cell communication modeling, we identified robust interactions between MDSCs and other cells, leading to NF-κB upregulation and an immunosuppressive microenvironment, as well as interactions involving regulatory T cells and osteosarcoma cells that promoted tumor progression and a proangiogenic niche. Full article
(This article belongs to the Special Issue Feature Papers in Section "Tumor Microenvironment")
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18 pages, 13680 KiB  
Article
Upregulated BAP31 Links to Poor Prognosis and Tumor Immune Microenvironment in Breast Cancer
by Zhenzhen Hao, Bo Zhao, Xiaoshuang Zhu, Wanting Zhang and Bing Wang
Int. J. Mol. Sci. 2025, 26(13), 5975; https://doi.org/10.3390/ijms26135975 - 21 Jun 2025
Viewed by 477
Abstract
BAP31, a transmembrane protein in the endoplasmic reticulum, is known for its oncogenic properties, but its role in immunotherapy is not well understood. While BAP31’s involvement in liver, gastric, and cervical cancers has been documented, its role in pan-cancer immune regulation, particularly in [...] Read more.
BAP31, a transmembrane protein in the endoplasmic reticulum, is known for its oncogenic properties, but its role in immunotherapy is not well understood. While BAP31’s involvement in liver, gastric, and cervical cancers has been documented, its role in pan-cancer immune regulation, particularly in breast cancer, remains unexplored. Using TCGA data, analysis via the Xiantao academic and GEPIA2 database showed that BAP31 upregulation correlates with advanced clinical stages and a poor prognosis. ROC analysis demonstrated BAP31’s high accuracy in distinguishing cancerous tissue from normal tissues. Additionally, BAP31 expression is associated with CNV, methylation, TMB, and MSI. In breast cancer, TIMER database analysis revealed that BAP31 expression is inversely correlated with the infiltration levels of myeloid-derived suppressor cells (MDSCs), macrophages, T lymphocytes, B lymphocytes, and neutrophils. Additionally, we investigated the relationship between BAP31 and the expression of major histocompatibility complex (MHC) molecules and chemokine receptors utilizing the TISIDB database. LinkedOmics analysis demonstrated associations between BAP31 and various immune-inflammatory pathways, while also indicating a negative correlation between BAP31 expression and four critical pathways: extracellular matrix receptor interaction, focal adhesion, JAK-STAT signaling, and TGF-β signaling. Furthermore, loss-of-function experiments employing shRNA-mediated knockdown of BAP31 resulted in a marked reduction in cell proliferation and an increase in apoptosis in breast cancer cells, thereby confirming its role in tumor promotion. These findings suggest that BAP31 may serve as a promising prognostic biomarker and a potential target for immunotherapy in breast cancer. Full article
(This article belongs to the Section Molecular Oncology)
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35 pages, 1619 KiB  
Review
Blood-Based Biomarkers as Predictive and Prognostic Factors in Immunotherapy-Treated Patients with Solid Tumors—Currents and Perspectives
by Franciszek Kaczmarek, Anna Marcinkowska-Gapińska, Joanna Bartkowiak-Wieczorek, Michał Nowak, Michał Kmiecik, Kinga Brzezińska, Mariusz Dotka, Paweł Brosz, Wojciech Firlej and Paulina Wojtyła-Buciora
Cancers 2025, 17(12), 2001; https://doi.org/10.3390/cancers17122001 - 16 Jun 2025
Viewed by 1059
Abstract
Immunotherapy has revolutionized cancer treatment; however, the availability of cost-effective blood-based biomarkers for prognostic and predictive factors of immune treatment in patients with solid tumors remains limited. Due to low cost and easy accessibility, blood-based biomarkers should constitute an essential component of studies [...] Read more.
Immunotherapy has revolutionized cancer treatment; however, the availability of cost-effective blood-based biomarkers for prognostic and predictive factors of immune treatment in patients with solid tumors remains limited. Due to low cost and easy accessibility, blood-based biomarkers should constitute an essential component of studies to optimize and monitor immunotherapy. Currently available markers that can be measured in peripheral blood include total monocyte count, myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), relative eosinophil count, cytokine levels (such as IL-6, IL-8, and IL-10), lactate dehydrogenase (LDH), C-reactive protein (CRP), soluble forms of CTLA-4 and PD-1 or PD-L1, as well as circulating tumor DNA (ctDNA). In our mini-review, we discuss the latest evidence indicating that routinely accessible peripheral blood parameters—such as the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and rheological parameters, which so far have been rarely considered for such an application, may be used as non-invasive biomarkers in cancer immunotherapy. Rheological parameters such as whole blood viscosity are influenced by several factors, such as hematocrit, aggregability and deformability of erythrocytes, and plasma viscosity, which is largely dependent on plasma proteins. Especially in cases where the set of symptoms indicates a high probability of hyperviscosity syndrome, blood rheological tests can lead to early diagnosis and treatment. Both biochemical and rheological parameters are prone to become novel and future standards for assessing immunotherapy among patients with solid tumors. Full article
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33 pages, 2687 KiB  
Review
Oxidized Low-Density Lipoprotein as a Potential Target for Enhancing Immune Checkpoint Inhibitor Therapy in Microsatellite-Stable Colorectal Cancer
by Xiaochun Zhang, Xiaorui Ye and Heiying Jin
Antioxidants 2025, 14(6), 726; https://doi.org/10.3390/antiox14060726 - 13 Jun 2025
Viewed by 1669
Abstract
Oxidized low-density lipoprotein (oxLDL) exhibits differential expression in microsatellite-stable (MSS) and microsatellite instability-high (MSI) colorectal cancer (CRC), highlighting its potential therapeutic role in immune checkpoint inhibitor (ICI) resistance in MSS CRC. Elevated oxLDL levels in MSS CRC contribute to tumor progression and diminish [...] Read more.
Oxidized low-density lipoprotein (oxLDL) exhibits differential expression in microsatellite-stable (MSS) and microsatellite instability-high (MSI) colorectal cancer (CRC), highlighting its potential therapeutic role in immune checkpoint inhibitor (ICI) resistance in MSS CRC. Elevated oxLDL levels in MSS CRC contribute to tumor progression and diminish ICI efficacy by modulating metabolic reprogramming and immunosuppressive mechanisms within the tumor microenvironment (TME) by activating receptors such as LOX-1 and CD36. oxLDL triggers signaling pathways, including NF-κB, PI3K/Akt, and MAPK, leading to the expansion of immunosuppressive cells like regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, while concurrently suppressing effector T cell functions. Additionally, oxLDL enhances oxidative stress and promotes fatty acid oxidation (FAO) and glycolytic metabolism, resulting in nutrient competition within the TME and establishing an immunosuppressive milieu, ultimately culminating in ICI resistance. This review systematically examines the disparities in oxLDL expression between MSS and MSI CRC and elucidates the molecular mechanisms through which oxLDL mediates ICI resistance. Furthermore, it explores potential therapeutic strategies targeting oxLDL, offering novel avenues to overcome immunotherapy resistance in MSS CRC. Full article
(This article belongs to the Special Issue Exploring Biomarkers of Oxidative Stress in Health and Disease)
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19 pages, 3450 KiB  
Article
BET Protein Inhibition Relieves MDSC-Mediated Immune Suppression in Chronic Lymphocytic Leukemia
by Erin M. Drengler, Audrey L. Smith, Sydney A. Skupa, Elizabeth Schmitz, Eslam Mohamed and Dalia El-Gamal
Hemato 2025, 6(2), 14; https://doi.org/10.3390/hemato6020014 - 24 May 2025
Viewed by 976
Abstract
Background: Myeloid-derived suppressor cells (MDSCs) contribute to immune suppression observed in chronic lymphocytic leukemia (CLL). MDSCs are immature myeloid cells that are hijacked during development and further reprogrammed by the tumor microenvironment (TME) to harbor immune-suppressive properties and inhibit T-cell functions. Bromodomain [...] Read more.
Background: Myeloid-derived suppressor cells (MDSCs) contribute to immune suppression observed in chronic lymphocytic leukemia (CLL). MDSCs are immature myeloid cells that are hijacked during development and further reprogrammed by the tumor microenvironment (TME) to harbor immune-suppressive properties and inhibit T-cell functions. Bromodomain and extraterminal domain (BET) proteins, including BRD4, are epigenetic modulators that regulate genes implicated in CLL pathogenesis and TME interactions. Previously, we investigated how the novel BET inhibitor OPN-51107 (OPN5) prevents CLL disease expansion, modulates T-cell immune function, and alters gene expression related to MDSCs. In turn, we hypothesize that BET proteins such as BRD4 regulate MDSC functions, and subsequent pharmacological inhibition of BRD4 will alleviate MDSC-mediated immune suppression in CLL. Methods: Utilizing the Eµ-TCL1 mouse model of CLL, we evaluated BRD4 protein expression in MDSCs derived from the bone marrow of transgenic and age-matched wild-type (WT) mice. We then investigated the ex vivo functionality of OPN5-treated MDSCs, expanded from Eµ-TCL1 and WT bone marrow in MDSC-supportive medium. Finally, we conducted an in vivo study utilizing the Eµ-TCL1 adoptive transfer mouse model to determine the in vivo effects of OPN5 on MDSCs and other immune populations. Results: Through the course of this study, we found that MDSCs isolated from Eμ-TCL1 mice upregulate BRD4 expression and are more immune-suppressive than their WT counterparts. Furthermore, we demonstrated ex vivo OPN5 treatment reverses the immune-suppressive capacity of MDSCs isolated from leukemic mice, evident via enhanced T-cell proliferation and IFNγ production. Finally, we showed in vivo OPN5 treatment slows CLL disease progression and modulates immune cell populations, including MDSCs. Conclusions: Altogether, these data support BET inhibition as a useful therapeutic approach to reverse MDSC-mediated immune suppression in CLL. Full article
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14 pages, 1255 KiB  
Review
The Relationships Among Perineural Invasion, Tumor–Nerve Interaction and Immunosuppression in Cancer
by Jozsef Dudas, Rudolf Glueckert, Maria do Carmo Greier and Benedikt Gabriel Hofauer
Onco 2025, 5(2), 25; https://doi.org/10.3390/onco5020025 - 23 May 2025
Viewed by 1331
Abstract
Tumor cells and the tumor microenvironment (TME) produce factors, including neurotrophins, that induce axonogenesis and neurogenesis, and increase local nerve density. Proliferative growing cancer cell clusters and disseminated invasive tumor cells undergoing partial epithelial-to-mesenchymal transition (pEMT) can invade peripheral nerves. In the early [...] Read more.
Tumor cells and the tumor microenvironment (TME) produce factors, including neurotrophins, that induce axonogenesis and neurogenesis, and increase local nerve density. Proliferative growing cancer cell clusters and disseminated invasive tumor cells undergoing partial epithelial-to-mesenchymal transition (pEMT) can invade peripheral nerves. In the early stages of tumor–nerve interactions, Schwann cells (SCs) dedifferentiate, become activated and migrate to cancer cell nests; later, they induce pEMT in tumor cells and activate tumor cell migration along nerves. The SC–tumor–nerve interaction attracts myeloid-derived suppressor cells (MDSCs) and inflammatory monocytes, and the latter differentiate into macrophages. SCs and MDSCs are responsible for the activation of transforming growth factor-beta (TGF-beta) signaling. Intra-tumoral innervation is followed by perineural invasion (PNI), which has an unfavorable prognosis. What are the interventional options against PNI: local reduction in tumor nerves or inhibition of TGF-beta-related events, inhibition of downstream signaling of TGF-beta or immune activation, or intervention against immunosuppression? This systematic review is based on the Prisma 2009 search method and provides an overview of tumor–nerve interaction. Full article
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35 pages, 5451 KiB  
Review
Innate Immunity and Platelets: Unveiling Their Role in Chronic Pancreatitis and Pancreatic Cancer
by Juliane Blümke, Moritz Schameitat, Atul Verma, Celina Limbecker, Elise Arlt, Sonja M. Kessler, Heike Kielstein, Sebastian Krug, Ivonne Bazwinsky-Wutschke and Monika Haemmerle
Cancers 2025, 17(10), 1689; https://doi.org/10.3390/cancers17101689 - 17 May 2025
Viewed by 1406
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic instability, acinar–ductal metaplasia, and pancreatic intraepithelial neoplasia (PanIN) formation. Components of the extracellular matrix, including immune cells, can modulate this progression phase. This includes cells of the innate immune system, such as natural killer (NK) cells, macrophages, dendritic cells, mast cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), either promoting or inhibiting tumor growth. On one hand, innate immune cells can trigger inflammatory responses that support tumor progression by releasing cytokines and growth factors, fostering tumor cell proliferation, invasion, and metastasis. On the other hand, they can also activate immune surveillance mechanisms, which can limit tumor development. For example, NK cells are cytotoxic innate lymphoid cells that are able to kill tumor cells, and active dendritic cells are crucial for a functioning anti-tumor immune response. In contrast, mast cells and MDSCs rather support a pro-tumorigenic tumor microenvironment that is additionally sustained by platelets. Once thought to play a role in hemostasis only, platelets are now recognized as key players in inflammation and cancer progression. By releasing cytokines, growth factors, and pro-angiogenic mediators, platelets help shape an immunosuppressive microenvironment that promotes fibrotic remodeling, tumor initiation, progression, metastasis, and immune evasion. Neutrophils and macrophages exist in different functional subtypes that can both act pro- and anti-tumorigenic. Understanding the complex interactions between innate immune cells, platelets, and early precursor lesions, as well as PDAC cells, is crucial for developing new therapeutic approaches that can harness the immune and potentially also the coagulation system to target and eliminate tumors, offering hope for improved patient outcomes. Full article
(This article belongs to the Special Issue Management of Pancreatic Cancer)
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25 pages, 5696 KiB  
Article
Constructing a Prognostic Model for Non-Small-Cell Lung Cancer Risk Based on Genes Characterising the Differentiation of Myeloid-Derived Suppressor Cells
by Yuheng Tang, Jianyu Pang, Yongzhi Chen, Qi Qi, Hui Wang, Yingjie Sun, Samina Gul, Xuhong Zhou and Wenru Tang
Int. J. Mol. Sci. 2025, 26(10), 4679; https://doi.org/10.3390/ijms26104679 - 14 May 2025
Viewed by 637
Abstract
Cancer is the most common malignancy, with over 2 million new cases and nearly 1.8 million deaths worldwide annually. Non-small-cell lung cancer (NSCLC) is the predominant subtype, accounting for the majority of cases. Myeloid-derived suppressor cells (MDSCs), which originate from monocytes and typically [...] Read more.
Cancer is the most common malignancy, with over 2 million new cases and nearly 1.8 million deaths worldwide annually. Non-small-cell lung cancer (NSCLC) is the predominant subtype, accounting for the majority of cases. Myeloid-derived suppressor cells (MDSCs), which originate from monocytes and typically differentiate into macrophages and granulocytes, possess potent immunosuppressive capabilities. MDSCs regulate immune responses in various pathological conditions and are strongly associated with poor prognosis in cancer patients. This study aims to elucidate the complex interplay between MDSCs, immune cells, and tumours in the NSCLC tumour microenvironment (TME). By integrating single-cell RNA sequencing (scRNA-seq) data with bulk RNA sequencing (Bulk RNA-seq) data, we identified MDSCs as the target cell population and used Monocle software (v2.22.0) to infer their developmental trajectories. We identified key genes associated with MDSCs differentiation processes and classified MDSCs into seven distinct states based on their functional roles. Furthermore, we constructed a prognostic risk model based on the impact of MDSCs differentiation on NSCLC prognosis, utilizing Elastic Net regression and multivariate Cox regression analysis of Bulk RNA-seq data. The model’s performance and accuracy were validated using both internal and external validation sets. Additionally, we compared risk scores with clinical pathological features and the relationship between risk scores and key immune cells in the immune microenvironment, demonstrating the model’s clinical predictive value. We also explored how prognostic genes contribute to poor prognosis in NSCLC. Moreover, small molecule compounds targeting these prognostic genes were screened, and their anti-tumour effects were evaluated as potential therapeutic strategies for NSCLC treatment. This study not only reveals the complex regulatory mechanisms of MDSCs in the NSCLC immune microenvironment but also successfully constructs a prognostic risk model based on MDSCs differentiation states. The model demonstrates excellent clinical performance in predicting patient prognosis, effectively identifying high-risk patients and providing robust support for individualized treatment and immunotherapy decisions. Through association analyses with key immune cells in the immune microenvironment and clinical pathological features, our model can assist clinicians in formulating more precise treatment plans based on patients’ immune status and tumour characteristics. Furthermore, we identified small molecule compounds targeting these prognostic genes, providing novel and promising therapeutic targets for NSCLC, which could further enhance treatment efficacy and improve patients’ survival quality. Full article
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23 pages, 1347 KiB  
Review
Harnessing Dendritic Cell Function in Hepatocellular Carcinoma: Advances in Immunotherapy and Therapeutic Strategies
by Shiding Ying, Haiyan Liu, Yongliang Zhang and Yu Mei
Vaccines 2025, 13(5), 496; https://doi.org/10.3390/vaccines13050496 - 4 May 2025
Cited by 1 | Viewed by 1453
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Conventional therapies are frequently limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Dendritic cells (DCs), central to orchestrating antitumor immunity, have become key targets for HCC immunotherapy. This review examines [...] Read more.
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Conventional therapies are frequently limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Dendritic cells (DCs), central to orchestrating antitumor immunity, have become key targets for HCC immunotherapy. This review examines the biological functions of DC subsets (cDC1, cDC2, pDC, and moDC) and their roles in initiating and modulating immune responses against HCC. We detail the mechanisms underlying DC impairment within the TME, including suppression by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). Additionally, we discuss novel DC-based therapeutic strategies, such as DC-based vaccines designed to enhance antigen presentation and T cell activation. Combining DC vaccines with immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 and CTLA-4 blockers, demonstrates synergistic effects that can overcome immune evasion and improve clinical outcomes. Despite progress, challenges related to DC subset heterogeneity, TME complexity, and patient variability require the further optimization and personalization of DC-based therapies. Future research should focus on refining these strategies, leveraging advanced technologies like genomic profiling and artificial intelligence, to maximize therapeutic efficacy and revolutionize HCC treatment. By restoring DC function and reprogramming the TME, DC-based immunotherapy holds immense potential to transform the management of HCC and improve patient survival. Full article
(This article belongs to the Special Issue Dendritic Cells (DCs) and Cancer Immunotherapy)
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