scholarly journals Glioblastoma: Relationship between Metabolism and Immunosuppressive Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3529
Author(s):  
Ainhoa Hernández ◽  
Marta Domènech ◽  
Ana M. Muñoz-Mármol ◽  
Cristina Carrato ◽  
Carmen Balana
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Treatment Response ◽  
Immune Cells ◽  
Genetic Alterations ◽  
Tumor Initiation ◽  
Immunosuppressive Microenvironment

Glioblastoma (GBM) is the most aggressive brain tumor in adults and is characterized by an immunosuppressive microenvironment. Different factors shaping this tumor microenvironment (TME) regulate tumor initiation, progression, and treatment response. Genetic alterations and metabolism pathways are two main elements that influence tumor immune cells and TME. In this manuscript, we review how both factors can contribute to an immunosuppressive state and overview the strategies being tested.

IMMU-14. REVEALING THE MANY MYELOID STATES IN HUMAN BRAIN TUMORS AND WAYS TO PERTURB THEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi94-vi95
Author(s):  
Tyler Miller ◽  
Chadi El Farran ◽  
Julia Verga ◽  
Charles Couturier ◽  
Zeyu Chen ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Human Tumor ◽  
Myeloid Cell ◽  
Low Grade ◽  
Tumor Patients ◽  
The Many

Abstract Recent breakthroughs in immunotherapy have revolutionized treatment for many types of cancer, but unfortunately trials of these therapies have failed to provide meaningful life-prolonging benefit for brain tumor patients, potentially due to abundant immunosuppressive myeloid cells in the tumor. Our ultimate goal is to reprogram immunosuppressive tumor associated myeloid cells to an antitumor state to enable effective immunotherapy. Towards this goal, we have deeply characterized the immune microenvironment of more than 50 primary high and low grade gliomas using high-throughput single-cell RNA-sequencing to reveal recurrent myeloid cell states and immunosuppressive programs across IDH1 wild-type and mutant tumors. We have also established a brain tumor organoid model from primary patient tissue that maintains all of the tumor microenvironment, including myeloid and other immune cells. We utilize the this model to functionally test data-driven reprogramming strategies and understand how they impact the states of tumor and immune cells in the ex vivo human tumor microenvironment.

scholarly journals IMMU-39. RNA LOADED LIPID-NANOPARTICLES FUNCTION AS CUSTOMIZABLE IMMUNOTHERAPEUTIC VEHICLES AGAINST MALIGNANT GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi127-vi127
Author(s):  
Adam Grippin ◽  
Brandon Wummer ◽  
Hector Mendez-Gomez ◽  
Brian Stover ◽  
Jianping Huang ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Lipid Nanoparticles ◽  
Lymphoid Organs ◽  
Innate Immune ◽  
T Cell Immunity ◽  
Innate Immune Cells ◽  
Cell Immunity ◽  
The Brain

Abstract BACKGROUND While dendritic cell (DC) vaccine therapy has shown considerable promise for glioblastoma (GBM) patients (Mitchell et al. Nature, 2015), their advancement into human clinical trials has been fraught with challenges in the development, manufacturing, and marketing of successful cancer immunotherapies. To circumvent the challenges associated with cell therapy, we have developed a new platform technology consisting of tumor derived mRNA complexed into lipid-nanoparticles (RNA-NPs) for systemic delivery to DCs in vivo and induction of antigen specific T cell immunity against GBM. OBJECTIVES/ METHODS We sought to assess if surface and charge modifications to our custom lipid-NP could facilitate its localization to lymphoid organs and the brain tumor microenvironment. RESULTS We demonstrate that intravenous administration of our unmodified custom RNA-NPs mediate systemic activation of DCs; these include activation of CD11c+ cells in the brains of animals with intact blood brain-barriers (BBBs). RNA-NPs mediate antigen specific T cell immunity and anti-tumor efficacy with increased tumor infiltrating lymphocytes against a NF-1/p53 mutant glioma that recapitulates features of human GBM in immunocompetent mice. Modification of surface charge could direct these RNA-NPs to lymphoid organs (e.g. spleen, lymph nodes) while modification of the lipid backbone (with cholesterol) enhances localization to innate immune cells in NF-1/p53 mutant and GL261 gliomas. We therefore assessed if this customizable lipid-NP could be leveraged for delivery of immune checkpoint inhibitors (ICIs) (i.e. PD-L1 siRNA) to the brain tumor microenvironment. Compared with scrambled siRNA-NPs in combination with ICIs, surface modified siRNA-NPs (antagonizing PD-L1) in combination with ICIs mediated significant antitumor efficacy with 37% long term survivors in an otherwise fatal brain tumor model. CONCLUSION We designed multifunctional RNA-NPs with a simple, scalable synthesis method that enables delivery of nucleic acids to innate immune cells in lymphoid organs and brain tumors.

scholarly journals TMIC-12. TUMOR-HOMING RNA-NANOPARTICLES REPROGRAM IMMUNE CELLS IN THE BRAIN TUMOR MICROENVIRONMENT

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi258-vi258
Author(s):  
Adam Grippin ◽  
Hector Mendez-Gomez ◽  
Brandon Wummer ◽  
Tyler Wildes ◽  
Kyle Dyson ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Tumor Homing ◽  
The Brain

scholarly journals Tissues and Tumor Microenvironment (TME) in 3D: Models to Shed Light on Immunosuppression in Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 831
Author(s):  
Teresa Ho ◽  
Rasha Msallam
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Cell ◽  
3D Models ◽  
Genetic Alterations ◽  
Experimental Models ◽  
Model Systems ◽  
Patient Specific ◽  
Great Promise ◽  
The Impact

Immunosuppression in cancer has emerged as a major hurdle to immunotherapy efforts. Immunosuppression can arise from oncogene-induced signaling within the tumor as well as from tumor-associated immune cells. Understanding various mechanisms by which the tumor can undermine and evade therapy is critical in improving current cancer immunotherapies. While mouse models have allowed for the characterization of key immune cell types and their role in tumor development, extrapolating these mechanisms to patients has been challenging. There is need for better models to unravel the effects of genetic alterations inherent in tumor cells and immune cells isolated from tumors on tumor growth and to investigate the feasibility of immunotherapy. Three-dimensional (3D) organoid model systems have developed rapidly over the past few years and allow for incorporation of components of the tumor microenvironment such as immune cells and the stroma. This bears great promise for derivation of patient-specific models in a dish for understanding and determining the impact on personalized immunotherapy. In this review, we will highlight the significance of current experimental models employed in the study of tumor immunosuppression and evaluate current tumor organoid-immune cell co-culture systems and their potential impact in shedding light on cancer immunosuppression.

scholarly journals Old Stars and New Players in the Brain Tumor Microenvironment

2021 ◽  
Vol 15 ◽  
Author(s):  
Elena Parmigiani ◽  
Marta Scalera ◽  
Elisabetta Mori ◽  
Elena Tantillo ◽  
Eleonora Vannini
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Glial Cells ◽  
Direct Interaction ◽  
Cell Types ◽  
Cellular Interactions ◽  
New Therapeutic Approaches ◽  
Promising Therapeutic Target ◽  
Resident Cell ◽  
Immunosuppressive Microenvironment

In recent years, the direct interaction between cancer cells and tumor microenvironment (TME) has emerged as a crucial regulator of tumor growth and a promising therapeutic target. The TME, including the surrounding peritumoral regions, is dynamically modified during tumor progression and in response to therapies. However, the mechanisms regulating the crosstalk between malignant and non-malignant cells are still poorly understood, especially in the case of glioma, an aggressive form of brain tumor. The presence of unique brain-resident cell types, namely neurons and glial cells, and an exceptionally immunosuppressive microenvironment pose additional important challenges to the development of effective treatments targeting the TME. In this review, we provide an overview on the direct and indirect interplay between glioma and neuronal and glial cells, introducing new players and mechanisms that still deserve further investigation. We will focus on the effects of neural activity and glial response in controlling glioma cell behavior and discuss the potential of exploiting these cellular interactions to develop new therapeutic approaches with the aim to preserve proper brain functionality.

scholarly journals Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma

2022 ◽  
Vol 11 ◽  
Author(s):  
Saket Jain ◽  
Eric J. Chalif ◽  
Manish K. Aghi
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Randomized Clinical Trials ◽  
Neutralizing Antibody ◽  
Tumor Vasculature ◽  
Tumor Evolution ◽  
Therapeutic Modalities ◽  
Angiogenic Therapy ◽  
T Cell Infiltration ◽  
Immunosuppressive Microenvironment

Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.

ROS-responsive nanomedicine: Towards targeting the breast tumor microenvironment

2020 ◽  
Vol 28 ◽  
Author(s):  
RamaRao Malla ◽  
Mohammad Amjad Kamal
Keyword(s):  
Reactive Oxygen Species ◽  
Gene Therapy ◽  
Drug Resistance ◽  
Molecular Imaging ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Breast Tumor ◽  
Imaging Techniques ◽  
Oxygen Species ◽  
Massive Accumulation

: The breast tumor microenvironment (TME) promotes drug resistance through an elaborated interaction of TME components mediated by reactive oxygen species (ROS). Despite a massive accumulation of data concerning the targeting the ROS, but little is known about the ROS-responsive nanomedicine for targeting breast TME. This review submits the ROS landscape in breast TME, including ROS biology, ROS mediated carcinogenesis, reprogramming of stromal and immune cells of TME. We also discussed ROS-based precision strategies for imaging TME, including molecular imaging techniques with advanced probes, multiplexed methods, and multi-omic profiling strategies. ROS-responsive nanomedicine also describes various therapies, such as chemo-dynamic, photodynamic, photothermal, sono-dynamic, immune, and gene therapy for BC. We expound ROS-responsive primary delivery systems for chemotherapeutics, phytochemicals, and immunotherapeutics. This review also presents recent updates on nano-theranostics for simultaneous diagnosis and treatment of BCs. We assume that review on this advancing field will be beneficial to the development of ROS-based nanotheranostics for BC.

Metabolism in the Tumor Microenvironment: What is Known about Stromal and Immune Cells?

2018 ◽  
Vol 4 (1) ◽  
Author(s):  
Mª Carmen Ocana ◽  
Beatriz Martinez-Poveda ◽  
Ana R. Quesada ◽  
Miguel Angel Medina
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells
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