International Journal of Molecular Sciences

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3 pages, 163 KiB

Open AccessEditorial

Macrophages in the Glioblastoma Tumor Microenvironment

by Salvatore J. Coniglio

Int. J. Mol. Sci. 2023, 24(10), 8978; https://doi.org/10.3390/ijms24108978 - 19 May 2023

Viewed by 1038

Abstract

The prognosis of high-grade glioma remains dismal, with the median survival time being 15 months [...] Full article

(This article belongs to the Special Issue Macrophages in the Glioblastoma Tumor Microenvironment)

Research

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11 pages, 2555 KiB

Open AccessArticle

The Chemokine Receptor CCR1 Mediates Microglia Stimulated Glioma Invasion

by Nazende Zeren, Zobia Afzal, Sara Morgan, Gregory Marshall, Maithrayee Uppiliappan, James Merritt and Salvatore J. Coniglio

Int. J. Mol. Sci. 2023, 24(6), 5136; https://doi.org/10.3390/ijms24065136 - 7 Mar 2023

Cited by 7 | Viewed by 2764

Abstract

Glioblastoma multiforme (GBM) is the most aggressive form of adult brain tumor which is highly resistant to conventional treatment and therapy. Glioma cells are highly motile resulting in infiltrative tumors with poorly defined borders. Another hallmark of GBM is a high degree of [...] Read more.

Glioblastoma multiforme (GBM) is the most aggressive form of adult brain tumor which is highly resistant to conventional treatment and therapy. Glioma cells are highly motile resulting in infiltrative tumors with poorly defined borders. Another hallmark of GBM is a high degree of tumor macrophage/microglia infiltration. The level of these tumor-associated macrophages/microglia (TAMs) correlates with higher malignancy and poorer prognosis. We previously demonstrated that inhibition of TAM infiltration into glioma tumors with the CSF-1R antagonist pexidartinib (PLX3397) can inhibit glioma cell invasion in-vitro and in-vivo. In this study, we demonstrate an important role for the chemokine receptor CCR1 in mediating microglia/TAM stimulated glioma invasion. Using two structurally distinct CCR1 antagonists, including a novel inhibitor “MG-1-5”, we were able to block microglial activated GL261 glioma cell invasion in a dose dependent manner. Interestingly, treatment of a murine microglia cell line with glioma conditioned media resulted in a strong induction of CCR1 gene and protein expression. This induction was attenuated by inhibition of CSF-1R. In addition, glioma conditioned media treatment of microglia resulted in a rapid upregulation of gene expression of several CCR1 ligands including CCL3, CCL5, CCL6 and CCL9. These data support the existence of tumor stimulated autocrine loop within TAMs which ultimately mediates tumor cell invasion. Full article

(This article belongs to the Special Issue Macrophages in the Glioblastoma Tumor Microenvironment)

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25 pages, 5707 KiB

Open AccessArticle

Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

by Martyn A. Sharpe, David S. Baskin, Amanda V. Jenson and Alexandra M. Baskin

Int. J. Mol. Sci. 2021, 22(20), 10983; https://doi.org/10.3390/ijms222010983 - 12 Oct 2021

Cited by 10 | Viewed by 3465

Abstract

Regulatory T-cells (Tregs) are immunosuppressive T-cells, which arrest immune responses to ‘Self’ tissues. Some immunosuppressive Tregs that recognize seminal epitopes suppress immune responses to the proteins in semen, in both men and women. We postulated that GBMs express reproductive-associated proteins to manipulate reproductive [...] Read more.

Regulatory T-cells (Tregs) are immunosuppressive T-cells, which arrest immune responses to ‘Self’ tissues. Some immunosuppressive Tregs that recognize seminal epitopes suppress immune responses to the proteins in semen, in both men and women. We postulated that GBMs express reproductive-associated proteins to manipulate reproductive Tregs and to gain immune privilege. We analyzed four GBM transcriptome databases representing ≈900 tumors for hypoxia-responsive Tregs, steroidogenic pathways, and sperm/testicular and placenta-specific genes, stratifying tumors by expression. In silico analysis suggested that the presence of reproductive-associated Tregs in GBM tumors was associated with worse patient outcomes. These tumors have an androgenic signature, express male-specific antigens, and attract reproductive-associated Related Orphan Receptor C (RORC)-Treg immunosuppressive cells. GBM patient sera were interrogated for the presence of anti-sperm/testicular antibodies, along with age-matched controls, utilizing monkey testicle sections. GBM patient serum contained anti-sperm/testicular antibodies at levels > six-fold that of controls. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are associated with estrogenic tumors which appear to mimic placental tissue. We demonstrate that RORC-Tregs drive poor patient outcome, and Treg infiltration correlates strongly with androgen levels. Androgens support GBM expression of sperm/testicular proteins allowing Tregs from the patient’s reproductive system to infiltrate the tumor. In contrast, estrogen appears responsible for MDSC/TAM immunosuppression. Full article

(This article belongs to the Special Issue Macrophages in the Glioblastoma Tumor Microenvironment)

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Review

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15 pages, 1269 KiB

Open AccessReview

Why Don’t the Mutant Cells That Evade DNA Repair Cause Cancer More Frequently? Importance of the Innate Immune System in the Tumor Microenvironment

by Shubhasmita Mohapatra, Jared Cafiero, Khosrow Kashfi, Parag Mehta and Probal Banerjee

Int. J. Mol. Sci. 2023, 24(5), 5026; https://doi.org/10.3390/ijms24055026 - 6 Mar 2023

Cited by 2 | Viewed by 2782

Abstract

The standard of care for most malignant solid tumors still involves tumor resection followed by chemo- and radiation therapy, hoping to eliminate the residual tumor cells. This strategy has been successful in extending the life of many cancer patients. Still, for primary glioblastoma [...] Read more.

The standard of care for most malignant solid tumors still involves tumor resection followed by chemo- and radiation therapy, hoping to eliminate the residual tumor cells. This strategy has been successful in extending the life of many cancer patients. Still, for primary glioblastoma (GBM), it has not controlled recurrence or increased the life expectancies of patients. Amid such disappointment, attempts to design therapies using the cells in the tumor microenvironment (TME) have gained ground. Such “immunotherapies” have so far overwhelmingly used genetic modifications of Tc cells (Car-T cell therapy) or blocking of proteins (PD-1 or PD-L1) that inhibit Tc-cell-mediated cancer cell elimination. Despite such advances, GBM has remained a “Kiss of Death” for most patients. Although the use of innate immune cells, such as the microglia, macrophages, and natural killer (NK) cells, has been considered in designing therapies for cancers, such attempts have not reached the clinic yet. We have reported a series of preclinical studies highlighting strategies to “re-educate” GBM-associated microglia and macrophages (TAMs) so that they assume a tumoricidal status. Such cells then secrete chemokines to recruit activated, GBM-eliminating NK cells and cause the rescue of 50–60% GBM mice in a syngeneic model of GBM. This review discusses a more fundamental question that most biochemists harbor: “since we are generating mutant cells in our body all the time, why don’t we get cancer more often?” The review visits publications addressing this question and discusses some published strategies for re-educating the TAMs to take on the “sentry” role they initially maintained in the absence of cancer. Full article

(This article belongs to the Special Issue Macrophages in the Glioblastoma Tumor Microenvironment)

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36 pages, 2978 KiB

Open AccessReview

Friends with Benefits: Chemokines, Glioblastoma-Associated Microglia/Macrophages, and Tumor Microenvironment

by Elena Codrici, Ionela-Daniela Popescu, Cristiana Tanase and Ana-Maria Enciu

Int. J. Mol. Sci. 2022, 23(5), 2509; https://doi.org/10.3390/ijms23052509 - 24 Feb 2022

Cited by 30 | Viewed by 5982

Abstract

Glioma is the most common primary intracranial tumor and has the greatest prevalence of all brain tumors. Treatment resistance and tumor recurrence in GBM are mostly explained by considerable alterations within the tumor microenvironment, as well as extraordinary cellular and molecular heterogeneity. Soluble [...] Read more.

Glioma is the most common primary intracranial tumor and has the greatest prevalence of all brain tumors. Treatment resistance and tumor recurrence in GBM are mostly explained by considerable alterations within the tumor microenvironment, as well as extraordinary cellular and molecular heterogeneity. Soluble factors, extracellular matrix components, tissue-resident cell types, resident or newly recruited immune cells together make up the GBM microenvironment. Regardless of many immune cells, a profound state of tumor immunosuppression is supported and developed, posing a considerable hurdle to cancer cells’ immune-mediated destruction. Several studies have suggested that various GBM subtypes present different modifications in their microenvironment, although the importance of the microenvironment in treatment response has yet to be determined. Understanding the microenvironment and how it changes after therapies is critical because it can influence the remaining invasive GSCs and lead to recurrence. This review article sheds light on the various components of the GBM microenvironment and their roles in tumoral development, as well as immune-related biological processes that support the interconnection/interrelationship between different cell types. Also, we summarize the current understanding of the modulation of soluble factors and highlight the dysregulated inflammatory chemokine/specific receptors cascades/networks and their significance in tumorigenesis, cancer-related inflammation, and metastasis. Full article

(This article belongs to the Special Issue Macrophages in the Glioblastoma Tumor Microenvironment)

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11 pages, 719 KiB

Open AccessReview

Tumor-Associated Macrophages/Microglia in Glioblastoma Oncolytic Virotherapy: A Double-Edged Sword

by Sarah E. Blitz, Ari D. Kappel, Florian A. Gessler, Neil V. Klinger, Omar Arnaout, Yi Lu, Pier Paolo Peruzzi, Timothy R. Smith, Ennio A. Chiocca, Gregory K. Friedman and Joshua D. Bernstock

Int. J. Mol. Sci. 2022, 23(3), 1808; https://doi.org/10.3390/ijms23031808 - 4 Feb 2022

Cited by 16 | Viewed by 3657

Abstract

Oncolytic virotherapy is a rapidly progressing field that uses oncolytic viruses (OVs) to selectively infect malignant cells and cause an antitumor response through direct oncolysis and stimulation of the immune system. Despite demonstrated pre-clinical efficacy of OVs in many cancer types and some [...] Read more.

Oncolytic virotherapy is a rapidly progressing field that uses oncolytic viruses (OVs) to selectively infect malignant cells and cause an antitumor response through direct oncolysis and stimulation of the immune system. Despite demonstrated pre-clinical efficacy of OVs in many cancer types and some favorable clinical results in glioblastoma (GBM) trials, durable increases in overall survival have remained elusive. Recent evidence has emerged that tumor-associated macrophage/microglia (TAM) involvement is likely an important factor contributing to OV treatment failure. It is prudent to note that the relationship between TAMs and OV therapy failures is complex. Canonically activated TAMs (i.e., M1) drive an antitumor response while also inhibiting OV replication and spread. Meanwhile, M2 activated TAMs facilitate an immunosuppressive microenvironment thereby indirectly promoting tumor growth. In this focused review, we discuss the complicated interplay between TAMs and OV therapies in GBM. We review past studies that aimed to maximize effectiveness through immune system modulation—both immunostimulatory and immunosuppressant—and suggest future directions to maximize OV efficacy. Full article

(This article belongs to the Special Issue Macrophages in the Glioblastoma Tumor Microenvironment)

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14 pages, 1667 KiB

Open AccessReview

The Eclectic Nature of Glioma-Infiltrating Macrophages and Microglia

by Víctor A. Arrieta, Hinda Najem, Edgar Petrosyan, Catalina Lee-Chang, Peiwen Chen, Adam M. Sonabend and Amy B. Heimberger

Int. J. Mol. Sci. 2021, 22(24), 13382; https://doi.org/10.3390/ijms222413382 - 13 Dec 2021

Cited by 16 | Viewed by 4189

Abstract

Glioblastomas (GBMs) are complex ecosystems composed of highly multifaceted tumor and myeloid cells capable of responding to different environmental pressures, including therapies. Recent studies have uncovered the diverse phenotypical identities of brain-populating myeloid cells. Differences in the immune proportions and phenotypes within tumors [...] Read more.

Glioblastomas (GBMs) are complex ecosystems composed of highly multifaceted tumor and myeloid cells capable of responding to different environmental pressures, including therapies. Recent studies have uncovered the diverse phenotypical identities of brain-populating myeloid cells. Differences in the immune proportions and phenotypes within tumors seem to be dictated by molecular features of glioma cells. Furthermore, increasing evidence underscores the significance of interactions between myeloid cells and glioma cells that allow them to evolve in a synergistic fashion to sustain tumor growth. In this review, we revisit the current understanding of glioma-infiltrating myeloid cells and their dialogue with tumor cells in consideration of their increasing recognition in response and resistance to immunotherapies as well as the immune impact of the current chemoradiotherapy used to treat gliomas. Full article

(This article belongs to the Special Issue Macrophages in the Glioblastoma Tumor Microenvironment)

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18 pages, 286 KiB

Open AccessReview

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

by Jun Ma, Clark C. Chen and Ming Li

Int. J. Mol. Sci. 2021, 22(11), 5775; https://doi.org/10.3390/ijms22115775 - 28 May 2021

Cited by 29 | Viewed by 4745

Abstract

The complex interaction between glioblastoma and its microenvironment has been recognized for decades. Among various immune profiles, the major population is tumor-associated macrophage, with microglia as its localized homolog. The present definition of such myeloid cells is based on a series of cell [...] Read more.

The complex interaction between glioblastoma and its microenvironment has been recognized for decades. Among various immune profiles, the major population is tumor-associated macrophage, with microglia as its localized homolog. The present definition of such myeloid cells is based on a series of cell markers. These good sentinel cells experience significant changes, facilitating glioblastoma development and protecting it from therapeutic treatments. Huge, complicated mechanisms are involved during the overall processes. A lot of effort has been dedicated to crack the mysterious codes in macrophage/microglia recruiting, activating, reprogramming, and functioning. We have made our path. With more and more key factors identified, a lot of new therapeutic methods could be explored to break the ominous loop, to enhance tumor sensitivity to treatments, and to improve the prognosis of glioblastoma patients. However, it might be a synergistic system rather than a series of clear, stepwise events. There are still significant challenges before the light of truth can shine onto the field. Here, we summarize recent advances in this field, reviewing the path we have been on and where we are now. Full article

(This article belongs to the Special Issue Macrophages in the Glioblastoma Tumor Microenvironment)

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