Exploiting the Cross-talk between Glioblastoma Cells and Tumor-associated Macrophages with a Nano-drug for regulating Tumor Immune Microenvironment

The majority of basic and clinical studies have shown a protumor function of tumor-associated macrophages (TAMs), which represent a large proportion of matrix cells. TAMs promote tumorigenesis, and their number is related to the malignancy degree and poor prognosis of many kinds of tumors. Macrophage plasticity makes it possible to change the tumor microenvironment and remodel antitumor immunity during cancer immunotherapy. Increasing numbers of studies have revealed the effects of TAMs on the tumor microenvironment, for example, via promotion of tumor growth and tumorigenesis and through an increase in the number of cancer stem cells or via facilitation of angiogenesis, lymphangiogenesis, and metastasis. Investigators also proposed tumor-immunological treatments targeting TAMs by inhibiting TAM recruitment and differentiation, by regulating TAM polarization, and by blocking factors and pathways associated with the protumor function of TAMs. This comprehensive review presents recent research on TAMs in relation to prediction of poor outcomes, remodeling of the tumor immune microenvironment, and immunological targeted therapies.

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Tumor-Associated Macrophages: Critical Players in Drug Resistance of Breast Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.799428 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maoyu Xiao ◽

Jun He ◽

Liyang Yin ◽

Xiguan Chen ◽

Xuyu Zu ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Therapeutic Strategies ◽

Tumor Associated Macrophages ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Potential Possibility ◽

Underlying Mechanisms ◽

Novel Therapeutic Strategies

Drug resistance is one of the most critical challenges in breast cancer (BC) treatment. The occurrence and development of drug resistance are closely related to the tumor immune microenvironment (TIME). Tumor-associated macrophages (TAMs), the most important immune cells in TIME, are essential for drug resistance in BC treatment. In this article, we summarize the effects of TAMs on the resistance of various drugs in endocrine therapy, chemotherapy, targeted therapy, and immunotherapy, and their underlying mechanisms. Based on the current overview of the key role of TAMs in drug resistance, we discuss the potential possibility for targeting TAMs to reduce drug resistance in BC treatment, By inhibiting the recruitment of TAMs, depleting the number of TAMs, regulating the polarization of TAMs and enhancing the phagocytosis of TAMs. Evidences in our review support it is important to develop novel therapeutic strategies to target TAMs in BC to overcome the treatment of resistance.

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Tumor-associated macrophages and the tumor immune microenvironment of primary and recurrent epithelial ovarian cancer

Human Pathology ◽

10.1016/j.humpath.2017.12.010 ◽

2018 ◽

Vol 74 ◽

pp. 135-147 ◽

Cited By ~ 15

Author(s):

Laureen S. Ojalvo ◽

Elizabeth D. Thompson ◽

Tian-Li Wang ◽

Alan K. Meeker ◽

Ie-Ming Shih ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Tumor Associated Macrophages ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment

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

10.1101/170282 ◽

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

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85 Spatial heterogeneity of tumor associated macrophages in the tumor immune microenvironment in ccRCC

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0085 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A94-A94

Author(s):

Nicholas Chakiryan ◽

Gregory Kimmel ◽

Youngchul Kim ◽

Jonathan Nguyen ◽

Jad Chahoud ◽

...

Keyword(s):

Spatial Heterogeneity ◽

Random Distribution ◽

Spatial Clustering ◽

Statistical Significance ◽

Point Pattern ◽

Tumor Associated Macrophages ◽

Immune Microenvironment ◽

Ripley’S K ◽

Ripley's K ◽

Tumor Immune Microenvironment

BackgroundTumor associated macrophages (TAM) stimulate tumor proliferation and facilitate immune escape via production of immunosuppressive cytokines. We hypothesize that non-random spatial clustering of TAMs within the tumor are associated with poor survival in ccRCC patients.MethodsTumor specimens were obtained from 41 patients with metastatic ccRCC who received immunotherapy (IT). Sections from the tumor core underwent multiplex immunofluorescence staining for CD68, CD163, and CD206. Digital pathologic analysis was used to convert the digital images to spatial point pattern plots (PPP). Ripley’s K function, the current standard metric for spatial heterogeneity, was utilized. Novel metrics were developed using a probability density function (PDF) for distances between cells, assuming that cells can be located anywhere with equal probability. Empirical histograms were generated from the PPPs. Deviation from the PDF demonstrates a non-random distribution. Deviations were quantified with the Kolmogorov-Smirnov (KS) test and Cramér-von Mises (CVM) criterion. Overall survival (OS) was assessed between groups stratified by the median value for each metric using Kaplan-Meier and log-rank analysis. Figure 1A.Results75 slides were analyzed from the 41 patients. The three metrics for measuring spatial heterogeneity had moderate and statistically significant correlation with each other (Spearman’s R: Ripley/KS=0.68, p<0.01; Ripley/CVM=0.54, p<0.01; KS/CVM=0.47, p<0.01; figure 1B). Using CVM, increasingly non-random distribution of the Tumor-CD68+ cell relationship was associated with worse OS (p<0.01, figure 1C), and increasingly non-random distribution of CD163+ cells suggested an association with worse OS without reaching statistical significance (p=0.06, figure 1C). No statistically significant associations were identified using the KS or Ripley’s K metrics.Abstract 85 Figure 1ConclusionsWe describe CVM and KS as novel metrics for measuring spatial heterogeneity of immune cells. Increased spatial heterogeneity of CD68+ TAMs and tumor cells was associated with worse OS in patients with metastatic ccRCC who received IT. These findings corroborate prior reports of TAMs eliciting an immunosuppressive effect on the tumor-immune microenvironment, and demonstrate the novel finding of a clinically significant effect of TAM spatial clustering on OS.

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