scholarly journals The effect of PEGylation on the efficacy and uptake of an immunostimulatory nanoparticle in the tumor immune microenvironment

2021 ◽  
Author(s):  
Wyatt M. Becicka ◽  
Peter Bielecki ◽  
Morgan Lorkowski ◽  
Taylor J. Moon ◽  
Yahan Zhang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Immunosuppressive Tumor Microenvironment

The efficacy of immunotherapies is often limited by the immunosuppressive tumor microenvironment, which is populated with dysfunctional innate immune cells. To reprogram the tumor-resident innate immune cells, we developed an...

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 Understanding the Role of Innate Immune Cells and Identifying Genes in Breast Cancer Microenvironment

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2226
Author(s):  
Israa Shihab ◽  
Bariaa A. Khalil ◽  
Noha Mousaad Elemam ◽  
Ibrahim Y. Hachim ◽  
Mahmood Yaseen Hachim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune System ◽  
Tumor Microenvironment ◽  
Nk Cells ◽  
Immune Cells ◽  
Innate Immune System ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Cancer Microenvironment

The innate immune system is the first line of defense against invading pathogens and has a major role in clearing transformed cells, besides its essential role in activating the adaptive immune system. Macrophages, dendritic cells, NK cells, and granulocytes are part of the innate immune system that accumulate in the tumor microenvironment such as breast cancer. These cells induce inflammation in situ by secreting cytokines and chemokines that promote tumor growth and progression, in addition to orchestrating the activities of other immune cells. In breast cancer microenvironment, innate immune cells are skewed towards immunosuppression that may lead to tumor evasion. However, the mechanisms by which immune cells could interact with breast cancer cells are complex and not fully understood. Therefore, the importance of the mammary tumor microenvironment in the development, growth, and progression of cancer is widely recognized. With the advances of using bioinformatics and analyzing data from gene banks, several genes involved in NK cells of breast cancer individuals have been identified. In this review, we discuss the activities of certain genes involved in the cross-talk among NK cells and breast cancer. Consequently, altering tumor immune microenvironment can make breast tumors more responsive to immunotherapy.

scholarly journals Iron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei Liang ◽  
Napoleone Ferrara
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Iron Metabolism ◽  
Immune Cells ◽  
Stromal Cells ◽  
Epidemiological Studies ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Cancer Initiation ◽  
Iron Binding Proteins

Cells of the innate immune system are a major component of the tumor microenvironment. They play complex and multifaceted roles in the regulation of cancer initiation, growth, metastasis and responses to therapeutics. Innate immune cells like neutrophils and macrophages are recruited to cancerous tissues by chemotactic molecules released by cancer cells and cancer-associated stromal cells. Once they reach the tumor, they can be instructed by a network of proteins, nucleic acids and metabolites to exert protumoral or antitumoral functions. Altered iron metabolism is a feature of cancer. Epidemiological studies suggest that increased presence of iron and/or iron binding proteins is associated with increased risks of cancer development. It has been shown that iron metabolism is involved in shaping the immune landscapes in inflammatory/infectious diseases and cancer-associated inflammation. In this article, we will dissect the contribution of macrophages and neutrophils to dysregulated iron metabolism in malignant cells and its impact on cancer growth and metastasis. The mechanisms involved in regulating the actions of macrophages and neutrophils will also be discussed. Moreover, we will examine the effects of iron metabolism on the phenotypes of innate immune cells. Both iron chelating and overloading agents are being explored in cancer treatment. This review highlights alternative strategies for management of iron content in cancer cells by targeting the iron donation and modulation properties of macrophages and neutrophils in the tumor microenvironment.

Regulation of tumor immune microenvironment by sphingolipids and lysophosphatidic acid

2021 ◽  
Vol 22 ◽  
Author(s):  
Supriya Vishwakarma ◽  
Neha Arya ◽  
Ashok Kumar
Keyword(s):  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Lysophosphatidic Acid ◽  
Immune Cells ◽  
Cancer Therapeutics ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Sphingosine 1 Phosphate ◽  
Patient Prognosis

: The tumor microenvironment (TME) consists of cancer cells that interact with stromal components such as the extracellular matrix, blood, and lymphatic networks, fibroblasts, adipocytes, and the cells of the immune system. Further, the tumor immune microenvironment, majorly represented by the tumor-infiltrating immune cells (TIIC), plays an important role in cancer therapeutics and patient prognosis. In fact, a high density of TIICs within the tumor microenvironment is known to be associated with better outcomes in several types of cancers. Towards this, two bioactive lipid molecules, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) regulate the homing of immune cells to the TME. In the present review, we will uncover the role of LPA and S1P signaling in the tumor immune environment, highlighting the latest progress in this field.

scholarly journals Comprehensive Analysis Identified ETV7 as a Potential Prognostic Biomarker in Bladder Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Haimeng Li ◽  
Yibo Zhang ◽  
Shangyong Zheng
Keyword(s):  
Bladder Cancer ◽  
Transcription Factor ◽  
Prognostic Factor ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Functional Enrichment ◽  
Immune Microenvironment ◽  
Gene Set ◽  
Tumor Immune Microenvironment ◽  
Low Expression

Background. The tumor microenvironment (TME) plays a crucial role in the initiation and progression of cancer. Bladder cancer (BLCA) is a malignant tumor of the genitourinary system. Its heterogeneity results in significant differences in the prognosis of patients. To date, this is still a huge challenge for clinical treatment. In recent years, more and more evidence showed that dysregulation of transcription factors (TFs) plays an important role in tumor progression, invasion, and metastasis. Unfortunately, the role of TFs on the tumor microenvironment in bladder cancer is unclear. Methods. The original data of BLCA and corresponding adjacent tissues were obtained from The Cancer Genome Atlas (TCGA) database. TFs were downloaded from the Animal Transcription Factor DataBase (Animal TFDB). Intersection analysis was used to obtain TFs that were differentially expressed between tumor and adjacent tissues. Gene Set Cancer Analysis (GSCALite) and CIBERSORT software were used to reveal the key differentially expressed TFs (DE-TFs). Subsequently, UALCAN and Human Protein Atlas (HPA) databases were used to disclose the expression of key DE-TFs in BLCA. The K - M curve divulged the relationship between the key DE-TFs and the patient’s overall survival (OS), and the univariate and multivariate Cox regression analyses were conducted to explore independent prognostic factors. The cluster profiler package and Gene Set Enrichment Analysis (GSEA) were used for functional enrichment of genes related to the key DE-TFs. Finally, CIBERSORT software analyzed the immune landscape of BLCA. Results. We obtained a total of 117 BLCA-related DE-TFs. Among them, ETV7 was identified as the key DE-TFs due to its association with the autophagy activation pathway and various immune cells in cancer. Online databases of UALCAN and HPA indicated that ETV7 was overexpressed in tumors and negatively correlated with tumor severity. The K - M curve showed that the OS of patients with high expression of ETV7 was poor, which indicated that it was an independent prognostic factor. Functional enrichment of 87 DEGs between ETV7-high and -low expression groups indicated that it was closely related to the immune response and the functions of a variety of immune cells. Finally, CIBERSORT results proved that the high and low expression of ETV7 also caused significant differences in the tumor immune microenvironment of patients. Conclusion. Overall, we proved that the transcription factor ETV7 was a novel prognostic factor, which may improve the individualized outcome prediction in BLCA by regulating the tumor immune microenvironment.

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