Precise regulation of inflammation and immunosuppressive microenvironment for amplified photothermal/immunotherapy against tumour recurrence and metastasis

Nano Today ◽  
2021 ◽  
Vol 40 ◽  
pp. 101266
Author(s):  
Yanbing Wang ◽  
Caina Xu ◽  
Meng Meng ◽  
Lin Lin ◽  
Yingying Hu ◽  
...  
Keyword(s):  
Tumour Recurrence ◽  
Immunosuppressive Microenvironment

scholarly journals Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Jianye Xu ◽  
Jian Zhang ◽  
Zongpu Zhang ◽  
Zijie Gao ◽  
Yanhua Qi ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Autophagy Induction ◽  
Antitumor Immunotherapy ◽  
Novel Biomarkers ◽  
And Migration ◽  
Immunosuppressive Microenvironment ◽  
Proliferation And Migration ◽  
Glioma Progression

AbstractExosomes participate in intercellular communication and glioma microenvironment modulation, but the exact mechanisms by which glioma-derived exosomes (GDEs) promote the generation of the immunosuppressive microenvironment are still unclear. Here, we investigated the effects of GDEs on autophagy, the polarization of tumor-associated macrophages (TAMs), and glioma progression. Compared with normoxic glioma-derived exosomes (N-GDEs), hypoxic glioma-derived exosomes (H-GDEs) markedly facilitated autophagy and M2-like macrophage polarization, which subsequently promoted glioma proliferation and migration in vitro and in vivo. Western blot and qRT-PCR analyses indicated that interleukin 6 (IL-6) and miR-155-3p were highly expressed in H-GDEs. Further experiments showed that IL-6 and miR-155-3p induced M2-like macrophage polarization via the IL-6-pSTAT3-miR-155-3p-autophagy-pSTAT3 positive feedback loop, which promotes glioma progression. Our study clarifies a mechanism by which hypoxia and glioma influence autophagy and M2-like macrophage polarization via exosomes, which could advance the formation of the immunosuppressive microenvironment. Our findings suggest that IL-6 and miR-155-3p may be novel biomarkers for diagnosing glioma and that treatments targeting autophagy and the STAT3 pathway may contribute to antitumor immunotherapy.

scholarly journals Prospects of immune checkpoint blockade and vaccine-based immunotherapy for glioblastoma

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Stefanie Tietze ◽  
Susanne Michen ◽  
Gabriele Schackert ◽  
Achim Temme
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Primary Brain Tumor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Therapeutic Vaccines ◽  
Dismal Prognosis ◽  
Tumor Parenchyma ◽  
Immunosuppressive Microenvironment

Abstract Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor endowed with a dismal prognosis. Nowadays, immunotherapy in a particular immune checkpoint blockade and therapeutic vaccines are being extensively pursued. Yet, several characteristics of GBM may impact such immunotherapeutic approaches. This includes tumor heterogeneity, the relatively low mutational load of primary GBM, insufficient delivery of antibodies to tumor parenchyma and the unique immunosuppressive microenvironment of GBM. Moreover, standard treatment of GBM, comprising temozolomide chemotherapy, radiotherapy and in most instances the application of glucocorticoids for management of brain edema, results in a further increased immunosuppression. This review will provide a brief introduction to the principles of vaccine-based immunotherapy and give an overview of the current clinical studies, which employed immune checkpoint inhibitors, oncolytic viruses-based vaccination, cell-based and peptide-based vaccines. Recent experiences as well as the latest developments are reviewed. Overcoming obstacles, which limit the induction and long-term immune response against GBM when using vaccination approaches, are necessary for the implementation of effective immunotherapy of GBM.

scholarly journals Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
J. I. Alexander ◽  
D. B. Vendramini-Costa ◽  
R. Francescone ◽  
T. Luong ◽  
J. Franco-Barraza ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Ductal Adenocarcinoma ◽  
Transforming Growth Factor Beta1 ◽  
Cancer Associated Fibroblast ◽  
Specific Tumor ◽  
Immunosuppressive Microenvironment ◽  
Anti Tumor Activity ◽  
Immunosuppressive Cytokines

AbstractPancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFβ1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFβ1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFβ1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.

Influence of positive margins on tumour recurrence and overall survival after gastrectomy for gastric cancer

2021 ◽  
Author(s):  
Luz Divina Juez ◽  
Alberto G. Barranquero ◽  
Pablo Priego ◽  
Marta Cuadrado ◽  
Luis Blázquez ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Tumour Recurrence ◽  
Positive Margins

scholarly journals Proteolysis-targeting chimera against BCL-XL destroys tumor-infiltrating regulatory T cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ryan Kolb ◽  
Umasankar De ◽  
Sajid Khan ◽  
Yuewan Luo ◽  
Myung-Chul Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Molecular Target ◽  
Therapeutic Strategies ◽  
Normal Tissues ◽  
Effective Suppression ◽  
Immunosuppressive Microenvironment ◽  
Cancer Immunotherapies

AbstractRegulatory T cells (Tregs) play an important role in maintaining immune homeostasis and, within tumors, their upregulation is common and promotes an immunosuppressive microenvironment. Therapeutic strategies that can eliminate Tregs in the tumor (i.e., therapies that do not run the risk of affecting normal tissues), are urgently needed for the development of cancer immunotherapies. Here we report our discovery of B-cell lymphoma extra-large (BCL-XL) as a potential molecular target of tumor-infiltrating (TI) Tregs. We show that pharmacological degradation of BCL-XL using a newly developed platelet-sparing BCL-XL Proteolysis-targeting chimera (PROTAC) induces the apoptosis of TI-Tregs and the activation of TI-CD8+ T cells. Moreover, these activities result in an effective suppression of syngeneic tumor growth in immunocompetent, but not in immunodeficient or CD8+ T cell-depleted mice. Notably, treatment with BCL-XL PROTAC does not cause detectable damage within several normal tissues or thrombocytopenia. These findings identify BCL-XL as a target in the elimination of TI-Tregs as a component of cancer immunotherapies, and that the BCL-XL-specific PROTAC has the potential to be developed as a therapeutic for cancer immunotherapy.

scholarly journals Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Luuk van Hooren ◽  
Alessandra Vaccaro ◽  
Mohanraj Ramachandran ◽  
Konstantinos Vazaios ◽  
Sylwia Libard ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Systemic Delivery ◽  
Systemic Induction ◽  
T Cell Infiltration ◽  
Treatment Naïve ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Immunosuppressive Microenvironment ◽  
The Brain ◽  
Opening Up

AbstractGliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.

scholarly journals Genetic program activity delineates risk, relapse, and therapy responsiveness in multiple myeloma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Matthew A. Wall ◽  
Serdar Turkarslan ◽  
Wei-Ju Wu ◽  
Samuel A. Danziger ◽  
David J. Reiss ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chromosomal Abnormalities ◽  
Transcriptional Regulatory Network ◽  
Progression Free Survival ◽  
Cross Sectional ◽  
Free Survival ◽  
Extreme Risk ◽  
Transcriptional Regulatory ◽  
Transcription Regulators ◽  
Immunosuppressive Microenvironment

AbstractDespite recent advancements in the treatment of multiple myeloma (MM), nearly all patients ultimately relapse and many become refractory to multiple lines of therapies. Therefore, we not only need the ability to predict which patients are at high risk for disease progression but also a means to understand the mechanisms underlying their risk. Here, we report a transcriptional regulatory network (TRN) for MM inferred from cross-sectional multi-omics data from 881 patients that predicts how 124 chromosomal abnormalities and somatic mutations causally perturb 392 transcription regulators of 8549 genes to manifest in distinct clinical phenotypes and outcomes. We identified 141 genetic programs whose activity profiles stratify patients into 25 distinct transcriptional states and proved to be more predictive of outcomes than did mutations. The coherence of these programs and accuracy of our network-based risk prediction was validated in two independent datasets. We observed subtype-specific vulnerabilities to interventions with existing drugs and revealed plausible mechanisms for relapse, including the establishment of an immunosuppressive microenvironment. Investigation of the t(4;14) clinical subtype using the TRN revealed that 16% of these patients exhibit an extreme-risk combination of genetic programs (median progression-free survival of 5 months) that create a distinct phenotype with targetable genes and pathways.

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