scholarly journals Harnessing the cross-talk between tumor cells and tumor-associated macrophages with a nano-drug for modulation of glioblastoma immune microenvironment

2017 ◽  
Vol 268 ◽  
pp. 128-146 ◽  
Author(s):  
Tong-Fei Li ◽  
Ke Li ◽  
Chao Wang ◽  
Xin Liu ◽  
Yu Wen ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cross Talk ◽  
Tumor Associated Macrophages ◽  
Immune Microenvironment ◽  
The Cross

scholarly journals Harnessing the Cross-talk between Tumor Cells and Tumor-associated Macrophages with a Nano-drug for modulation of Glioblastoma Immune Microenvironment

2017 ◽  
Author(s):  
Tong-Fei Li ◽  
Ke Li ◽  
Chao Wang ◽  
Xin Liu ◽  
Yu Wen ◽  
...  
Keyword(s):  
Cross Talk ◽  
Culture Medium ◽  
Enzyme Linked Immunosorbent Assay ◽  
Immune Microenvironment ◽  
Potent Inducer ◽  
The Cross ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

AbstractGlioblastoma (GBM) is the most frequent and malignant brain tumor with a high mortality rate. The presence of a large population of macrophages (Mφ) in the tumor microenvironment is a prominent feature of GBM and these so-called tumor-associated Mφ (TAM) closely interact with the GBM cells to promote the survival, progression and therapy resistance of the GBM. Various therapeutic strategies have been devised either targeting the GBM cells or the TAM but few have addressed the cross-talks between the two cell populations. The present study was carried out to explore the possibility of exploiting the cross-talks between the GBM cells (GC) and TAM for modulation of the GBM microenvironment through using Nano-DOX, a drug composite based on nanodiamonds bearing doxorubicin. In the in vitro work on human cell models, Nano-DOX-loaded TAM were first shown to be viable and able to infiltrate three-dimensional GC spheroids and release cargo drug therein. GC were then demonstrated to encourage Nano-DOX-loaded TAM to unload Nano-DOX back into GC which consequently emitted damage-associated molecular patterns (DAMPs) that are powerful immunostimulatory agents as well as indicators of cell damage. Nano-DOX was next proven to be a more potent inducer of GC DAMPs emission than doxorubicin. As a result, Nano-DOX-damaged GC exhibited an enhanced ability to attract both TAM and Nano-DOX-loaded TAM. Most remarkably, Nano-DOX-damaged GC reprogrammed the TAM from a pro-GBM phenotype to an anti-GBM phenotype that suppressed GC growth. Finally, the in vivo relevance of the in vitro findings was tested in animal study. Mice bearing orthotopic human GBM xenografts were intravenously injected with Nano-DOX-loaded mouse TAM which were found releasing drug in the GBM xenografts 24 h after injection. GC damage was evidenced by the induction of DAMPs emission within the xenografts and a shift of TAM phenotype was detected as well. Taken together, our results demonstrate a novel way with therapeutic potential to harness the cross-talk between GBM cells and TAM for modulation of the tumor immune microenvironment.AbbreviationsATP, adenosine triphosphate; BBB, blood-brain barrier; BCA, bicinchoninic acid; BMDM, bone marrow derived macrophages; CD, cluster of differentiation; CFSE, 5(6)-carboxyfluorescein diacetate, succinimidyl ester; CM, conditioned culture medium; CNS, central nervous system; CRT, calreticulin; DAMPs, damage-associated molecular patterns; DAB, diaminobenzidine; DOX, doxorubicin; ECL, enhanced chemiluminescence; ELISA, enzyme-linked immunosorbent assay; HMGB1, high mobility group protein B1; HSP90, heat shock protein 90; FACS, flow cytometry; GBM, glioblastoma; Guanylate Binding Protein 5 (GBP5); GC, glioblastoma cells; IHC, immunohistochemical; IL, interleukin; Mφ, macrophages; mBMDM, mouse BMDM; mBMDM2, Type-2 mBMDM; M1, Type-1 Mø; M2, Type-2 Mø; Nano-DOX, ND-PG-RGD-DOX; ND, nanodiamonds; Nano-DOX-mBMDM, Nano-DOX-loaded mouse BMDM; NGCM, Nano-DOX-treated-GC-conditioned medium; PBS, phosphate buffered saline; PG, polyglycerol; PMA, phorbol 12-myristate 13-acetate; PVDF, polyvinylidene fluoride; RGD, tripeptide of L-arginine, glycine and L-aspartic acid; RM, regular culture medium; SD, standard deviation; TAM, tumor-associated Mφ; TBST, Tris Buffered Saline with Tween® 20.Graphic abstract

scholarly journals The Cross Talk between Cancer Stem Cells/Cancer Initiating Cells and Tumor Microenvironment: The Missing Piece of the Puzzle for the Efficient Targeting of these Cells with Immunotherapy

2019 ◽  
Vol 12 (2-3) ◽  
pp. 133-148 ◽  
Author(s):  
Shilpa Ravindran ◽  
Saad Rasool ◽  
Cristina Maccalli
Keyword(s):  
Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Cross Talk ◽  
Tumor Formation ◽  
Mutual Interaction ◽  
Immunological Profile ◽  
The Cross ◽  
Cancer Immunosurveillance

AbstractCancer Stem Cells/Cancer Initiating Cells (CSCs/CICs) is a rare sub-population within a tumor that is responsible for tumor formation, progression and resistance to therapies. The interaction between CSCs/CICs and tumor microenvironment (TME) can sustain “stemness” properties and promote their survival and plasticity. This cross-talk is also pivotal in regulating and modulating CSC/CIC properties. This review will provide an overview of the mechanisms underlying the mutual interaction between CSCs/CICs and TME. Particular focus will be dedicated to the immunological profile of CSCs/CICs and its role in orchestrating cancer immunosurveillance. Moreover, the available immunotherapy strategies that can target CSCs/CICs and of their possible implementation will be discussed. Overall, the dissection of the mechanisms regulating the CSC/CIC-TME interaction is warranted to understand the plasticity and immunoregulatory properties of stem-like tumor cells and to achieve complete eradications of tumors through the optimization of immunotherapy.

Dual Face of Immune Microenvironment in Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-50-SCI-50
Author(s):  
Madhav V. Dhodapkar
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Immune System ◽  
Natural Killer ◽  
Tumor Cells ◽  
Genomic Instability ◽  
Tumor Immunity ◽  
Cross Talk ◽  
Immune Microenvironment ◽  
Growth Of Tumor

An important property of human multiple myeloma (MM) is the growth of tumor cells and their precursors in the bone marrow microenvironment. This specialized microenvironment includes a distinct component of immune cells that includes cells of innate as well as adaptive immune system. Growing body of evidence points to a central role for cross-talk between this immune microenvironment and tumor cells in regulating the growth of tumor cells in myeloma. These interactions play a dual role-with some interactions promoting tumor growth while others suppress growth of tumor cells. Cross talk between T and B cells has been implicated in normal B/plasma cell differentiation and may also play a role in pathogenesis of myeloma, explaining increased risk of plasma cell malignancies in certain settings such as Gaucher disease. The bone marrow of MM patients is often infiltrated with innate cells such as dendritic cells (DCs) and cross-talk between myeloid/plasmacytoid DCs or macrophages may promote growth and survival of MM cells. This cross-talk may also have fundamental implications for inducing genomic instability in tumor cells, such as via the induction of cytidine deaminases in tumor cells. Genomic instability is an early feature of human MM and many of the mutations found in MM tumor cells are also present in the precursor states. The immune system has the capacity to recognize these precursor lesions and even in the setting of clinical MM, the tumor bed contains T cells that can be recruited to kill tumor cells. Specific targets of tumor immunity may differ between preclinical and clinical malignancy. Immunity to certain stem cell-associated antigens are in particular associated with reduced risk of progression to clinical MM. With advanced disease, tumor infiltrating T cells encounter several immune inhibitory checkpoints which leads to suppression of function of tumor-infiltrating T cells. In addition to T cells, cells of the innate immune system such as natural killer and natural killer T cells may also be attractive targets of protective tumor immunity in MM. Immunologic approaches may also be combined with other strategies such as other immunomodulatory drugs (IMiDs) already in clinical use in MM. Recent advances in mouse modeling provide new opportunities to better understand how to harness the immune system against human MM. Such approaches have the advantage of the potential for durable control of tumor cells via immunologic memory. Such approaches are now entering the clinic as attractive targets to restore anti-tumor immunity, both in the context of therapy or prevention of MM. Disclosures Dhodapkar: Celgene: Research Funding. Off Label Use: checkpoint blockade drugs, imids.

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