Predominance of M2 macrophages in gliomas leads to the suppression of local and systemic immunity

Vidyarthi, Aurobind; Agnihotri, Tapan; Khan, Nargis; Singh, Sanpreet; Tewari, Manoj Kumar; Radotra, Bishan Das; Chatterjee, Deepyan; Agrewala, Javed N.

doi:10.1007/s00262-019-02423-8

Cited by 101 publications

(80 citation statements)

References 31 publications

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“…However, we did not observe any differences in the CD163 expression among the monocytes present in the blood of the same individuals. In fact, we did not observe a higher proportion of CD163 expressing monocytes in the blood of individuals with glioma when compared to healthy controls too, which appears to be contrary to previous reports by Heimberger and colleagues 19 and Agrewala and colleagues 21 . But it is important to note the following differences: the former study compared the expression levels of CD163 at the RNA level, while the latter study used a different gating strategy (CD11b vs. CD14 used by us).…”

Section: Discussioncontrasting

confidence: 99%

“…For example, larger numbers of myeloid-derived suppressor cells (MDSCs) have been observed in the blood [12][13][14][15] , and these cells are also enriched in the GBM microenvironment 5,[16][17][18] . An enrichment of suppressive monocyte/macrophages (M2 or M0 phenotype) 10,[19][20][21] has also been observed. Further, it has been suggested that the monocytes in the GBM microenvironment may be phenotypically and functionally different 22,23 , and the same is possibly true for neutrophils [24][25][26] too.…”

Section: Introductionmentioning

confidence: 84%

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Immuno-Phenotyping of High-Grade Glioma Infiltrating Immune Cells Reveals Grade Specific Differences in Cells of Myeloid Origin

Ganesh

Raghavan

Sonpatki

et al. 2020

Preprint

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Gliomas are heavily infiltrated with immune cells of myeloid origin. Past studies have shown that high-grade gliomas have a higher proportion of alternatively activated and suppressive myeloid cells when compared to low-grade gliomas, which correlate with poor prognosis. However, the differences in immune cell phenotypes within high-grade gliomas (between grade III and IV) are relatively less explored, and a correlation of phenotypic characteristics between immune cells in the blood and high grade tumors has not been performed. Additionally, myeloid cells of granulocytic origin present in gliomas remain poorly characterized. Herein, we address these questions through phenotypic characterizations of monocytes and neutrophils present in blood and tumors of individuals with glioblastoma (GBM, grade IV) or grade III gliomas. Our data show that CD163 expressing M2 monocytes are present in greater proportions in GBM tissue when compared to grade III glioma tissue. In addition, we observe that neutrophils are highly heterogeneous among individuals with glioma, and a greater proportion of granulocytic myeloid-derived suppressor cells are present in grade III gliomas when compared to GBM. Finally, we show that the expression levels of CD86 and CD63 showed a high correlation between blood and tumor, and suggest that these may be used as possible markers for prognosis.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 84%

Immuno-Phenotyping of High-Grade Glioma Infiltrating Immune Cells Reveals Grade Specific Differences in Cells of Myeloid Origin

Ganesh

Raghavan

Sonpatki

et al. 2020

Preprint

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“…Our novel findings of the higher density of B cells in tumors from female patients are reflective of the established physiological links between M2-like TAMs and B cells [21]; co-stimulation of M2like macrophages with bacterial lipopolysaccharide and IL-10 induces production of CXCL13, a chemokine critical for B cell recruitment [22,23]. Given the increased incidence of urinary tract infections in women -and the cancer cell-induced polarization of TAMs towards an M2-like phenotype [19] -it is plausible that increased engagement of M2-like TAMs by urinary pathogens leads to increased CXCL13 secretion and B cell recruitment in tumors of female NMIBC patients.…”

Section: Discussionmentioning

confidence: 71%

Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

Chenard

Jackson

Vidotto

et al. 2021

Preprint

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Non-muscle invasive bladder cancer (NMIBC) is significantly more common in men than women. However, female patients with NMIBC often present with more aggressive disease and do not respond as well to immunotherapy treatments. We hypothesized that sexual dimorphism in the tumor immune microenvironment (TIME) may contribute to the inferior clinical outcomes observed in female patients. To test this hypothesis, we interrogated the expression patterns of genes associated with specific immune cell types and immune regulatory pathways using tumor whole transcriptome profiles from male (n=357) and female (n=103) patients with NMIBC. High-grade tumors from female patients exhibited significantly increased expression of CD40, CTLA4, PDCD1, LAG3 and ICOS immune checkpoint genes. Based on the significant differences in expression profiles of these genes and the cell types that most commonly express these in the TIME, we evaluated the density and spatial distribution of CD8+Ki67+ (activated cytotoxic T cells), FoxP3+ (regulatory T cells), CD103+ (tissue resident T cells), CD163+ (M2-like tumor associated macrophages), CD79a+ (B cells), PD-L1+ (Programmed-Death Ligand-1) and PD-1+ cells using multiplexed immunofluorescence in an independent cohort of 332 patient tumors on a tissue microarray (n=259 males and n=73 females). Tumors from female patients showed significantly higher infiltration of CD163+ macrophages and PD-L1+ cells compared to tumors from male patients. Notably, increased infiltration of CD163+ macrophages and CD79a+ B cells independently associated with decreased recurrence free survival. Not only do these results have the potential to inform the rational utilization of immunomodulatory therapies based on the TIME of both male and female patients with NMIBC, these novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials.

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“…Moreover, Sorensen et al demonstrated that M2-like TAMs are associated with more aggressive tumors and can predict worse prognosis in high-grade glioma [ 74 ]. High gene expression ratio of CD163/CCL3 in gliomas, as M2 and M1 macrophage markers, respectively, and PD-1+ CD4 T cells in the blood of tumor patients were associated with poor prognosis [ 75 ]. Increased numbers of CD68+ and higher ratio of CD163/AIF+ cells, as TAMs markers, and more FOXP3+ cells were associated with shorter progression-free survival, while high CD3+ and CD8+ T cells accompanied by low CD68+ and high IDO+ cell counts were associated with better glioma prognosis [ 76 ].…”

Section: Gliomasmentioning

confidence: 99%

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

Belgiovine

Digifico

Anfray

et al. 2020

JCM

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In the last decade, it has been well-established that tumor-infiltrating myeloid cells fuel not only the process of carcinogenesis through cancer-related inflammation mechanisms, but also tumor progression, invasion, and metastasis. In particular, tumor-associated macrophages (TAMs) are the most abundant leucocyte subset in many cancers and play a major role in the creation of a protective niche for tumor cells. Their ability to generate an immune-suppressive environment is crucial to escape the immune system and to allow the tumor to proliferate and metastasize to distant sites. Conventional therapies, including chemotherapy and radiotherapy, are often not able to limit cancer growth due to the presence of pro-tumoral TAMs; these are also responsible for the failure of novel immunotherapies based on immune-checkpoint inhibition. Several novel therapeutic strategies have been implemented to deplete TAMs; however, more recent approaches aim to use TAMs themselves as weapons to fight cancer. Exploiting their functional plasticity, the reprogramming of TAMs aims to convert immunosuppressive and pro-tumoral macrophages into immunostimulatory and anti-tumor cytotoxic effector cells. This shift eventually leads to the reconstitution of a reactive immune landscape able to destroy the tumor. In this review, we summarize the current knowledge on strategies able to reprogram TAMs with single as well as combination therapies.

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Predominance of M2 macrophages in gliomas leads to the suppression of local and systemic immunity

Cited by 101 publications

References 31 publications

Immuno-Phenotyping of High-Grade Glioma Infiltrating Immune Cells Reveals Grade Specific Differences in Cells of Myeloid Origin

Immuno-Phenotyping of High-Grade Glioma Infiltrating Immune Cells Reveals Grade Specific Differences in Cells of Myeloid Origin

Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

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