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


Glioblastoma is a highly prevalent and aggressive form of primary brain tumor. It represents approximately 56% of all the newly diagnosed gliomas. Macrophages are one of the major constituents of tumor-infiltrating immune cells in the human gliomas. The role of immunosuppressive macrophages is very well documented in correlation with the poor prognosis of patients suffering from breast, prostate, bladder and cervical cancers. The current study highlights the correlation between the tumor-associated macrophage phenotypes and glioma progression. We observed an increase in the pool of M2 macrophages in high-grade gliomas, as confirmed by their CD68 and CD163 double-positive phenotype. In contrast, less M1 macrophages were noticed in high-grade gliomas, as evidenced by the down-regulation in the expression of CCL3 marker. In addition, we observed that higher gene expression ratio of CD163/CCL3 is associated with glioma progression. The Kaplan–Meier survival plots indicate that glioma patients with lower expression of M2c marker (CD163), and higher expression of M1 marker (CCL3) had better survival. Furthermore, we examined the systemic immune response in the peripheral blood and noted a predominance of M2 macrophages, myeloid-derived suppressor cells and PD-1+ CD4 T cells in glioma patients. Thus, the study indicates a high gene expression ratio of CD163/CCL3 in high-grade gliomas as compared to low-grade gliomas and significantly elevated frequency of M2 macrophages and PD-1+ CD4 T cells in the blood of tumor patients. These parameters could be used as an indicator of the early diagnosis and prognosis of the disease.

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Fluorescence-activated cell sorting


Glyceraldehyde 3-phosphate dehydrogenase


High-grade glioma


Human Leukocyte Antigen—DR isotype


Interferon gamma


Interleukin 10


Interleukin-10 receptor


Low-grade glioma




Peripheral blood mononuclear cells


Phosphate-buffered saline


Programmed cell death protein 1


Tumor-associated macrophages


The Cancer Genome Atlas


Transforming growth factor-beta


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We thank Dr. Debajyoti Chatterjee, Gurpreet, Ishwar and Alka from Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India for the helpful suggestions for doing immunohistochemistry.


Authors are grateful to the Council of Scientific and Industrial Research (CSIR), Department of Biotechnology (DBT), Indian Council of Medical Research (ICMR), India for financial support. Aurobind Vidyarthi and Tapan Agnihotri received fellowships from the CSIR, Nargis Khan from DBT, and Sanpreet Singh from ICMR.

Author information




JNA and AV conceived the project. AV, TA and NK performed experiments. AV, TA, NK, JNA, BDR, MKT and DC analyzed data. AV, JNA, NK, MKT and SS wrote the manuscript. All authors assisted in editing the manuscript and approved its final version.

Corresponding author

Correspondence to Javed N. Agrewala.

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Competing interests

All authors have declared no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional committee. The study was approved by the Postgraduate Institute of Medical Education and Research, Chandigarh, India ‘Institutional Ethical Committee’ (Ref. No. PGI/IEC/2012/1498-99) and ‘Institutional Biosafety Committee of the Institute of Microbial Technology’ (Ref. No. 1/IEC/1/9-2014), Chandigarh, India.

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Written informed consent was obtained from all individual participants and close relative of the deceased (For cadavers) included in the study for using the specimens for research and publication.

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Vidyarthi, A., Agnihotri, T., Khan, N. et al. Predominance of M2 macrophages in gliomas leads to the suppression of local and systemic immunity. Cancer Immunol Immunother 68, 1995–2004 (2019).

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  • Glioma
  • Tumor-associated macrophages
  • CD163
  • CCL3
  • PD-1