BRAIN TUMOR AND INFLAMMATION

M.L. Castellani

Immunology Division, University of Chieti, 66100 Chieti, Italy.

*Correspondence to:
M.L. Castellani, PhD
Immunology Division,
University of Chieti,
66100 Chieti, Italy.
e-mail: mlcastellani@unich.it

Received: 02 September 2017 Accepted: 26  October  2017

2279-5855 (2017) Copyright © by BIOLIFE This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Innate immunity generates cytokines, including IL-1, which are important in controlling tumor development. Excessive synthesis and secretion of pro-inflammatory cytokines causes inflammation that promotes tumor development and progression. Immune cells are present in tumor tissue, including lymphocytes and monocytes that generate cytokines. These immune cells are recruited to the tumor site to fight the new tumor tissue which is not recognized as self. However, this process leads to a production of chemokines which attract immune cells, producing an excess of inflammatory cytokines that favor tumor development. Mast cells (MCs) are ubiquitous immune cells that also reside in brain tissue and participate in the brain tumor process by generating neuroinflammation. MCs are recruited by chemokines into brain tumor tissue where they become activated and produce several cytokines including IL-8, growth factors, vascular endothelial growth factor (VEGF), and also chemical mediators such as histamine and heparin, and tryptase and chymase that favor the formation of new blood vessels and mediate the production of metastases. However, MC accumulation in cancer tissue can be either beneficial or detrimental for tumor development.

KEYWORDS: brain, tumor, inflammation, cytokines, chemokines, immune response

INTRODUCTION

Chronic brain inflammation is mediated by cytokines and chemokines, which are generated by innate immunity and can have effects on the growth of tumors (1,2). This demonstrates the close connection between cancer and inflammation (3). Neuroinflammation and pain are characteristic and fundamental symptoms of the central and peripheral nervous systems. The brain has non-neuronal cells such as glial cells and keratinocytes that play an important role in the pathogenesis of diseases, including cancer. In recent years, much has been learned about the immune response to brain tumors and it has been seen that inflammation plays an important role both in the central nervous system (CNS) (4) and in other areas of the body.

Experimental and clinical studies have shown that tumor development is related to the host’s immune response (5,6). In fact, histological analyses of tumor tissue shows the presence of immune cells surrounding the tumor mass (7). Immune cells, such as lymphocytes and monocytes, generate inflammatory cytokines in tumor tissue, including brain tissue (8). The inflammation produced by the excessive production and secretion of pro-inflammatory cytokines promotes the development and progression of tumors.

DISCUSSION

In brain tumor tissue, there are immune cells such as lymphocytes and monocytes that are recruited to the tumor site in response to new tissue that is recognized as non-self. These immune cells generate cytokines and produce chemokines which attract further immune cells, producing an excess of inflammatory cytokines that exacerbates tumor development (9).

In brain tumors, immune cells, and particularly Th1 cells which physiologically monitor and maintain neuronal integrity, are activated (10). In glioma tumors, microglial cells and macrophages make up approximately 30% of the inflammatory cells in the brain (11). Inflammation in brain tumors manifests with edema (containing inflammatory proteins) which causes an increase in intracranial pressure and compromises the circulation of cerebrospinal fluid (CSF) (12). This phenomenon can give rise to hydrocephalus, resulting in headaches, hypertension, and shock, a life-threatening event. CNS tumors are often accompanied by fever and headache which represent the response to the inflammatory state (13,14).

Immunotherapy is a biological strategy that trains the immune system to recognize tumor neoantigens generated by genetic mutations. The activation of effector T lymphocytes plays an important role in homeostasis and in combating specific antigens, although excessive stimulation can induce an autoimmune phenomenon (15). In tumors, fever is caused by brain inflammation (called sterile inflammation), which should not be confused with fever that is induced by microorganisms. It has been reported that pro-inflammatory cytokines promote tumor cell development and play an important role in brain pathogenesis. Inflammatory cytokines contribute to brain tumor invasion and metastasis through the induction of metalloproteinases (16). In addition, inflammatory cytokines such as IL-1 and tumor necrosis factor (TNF) can have an autocrine effect, aggravating tumorigenic activity (17).

In the brain, proliferative and invasive tumors develop using non-transforming cells and chemoattracting molecules such as chemokines (18). These molecules are a subfamily of cytokines that have the ability to migrate and exert their biological effects through their specific transmembrane receptors (19). They are classified into C, CC, CX3C, and CXC categories based on the cysteine position on their molecular structure (20). The chemokines CCL2 and CXCL8 belong to the CXC subgroup and are produced by glial cells that express their receptors. These chemokines mediate diverse biological effects, including angiogenesis, invasiveness, proliferation, and cell survival (Table I).

Table I. Some of the biological effects that are mediated by certain chemokines.

Mast cells (MCs) are ubiquitous immune cells that are involved in innate and adaptive immunity. They are classic cells known to mediate allergic diseases and also participate in the development of brain tumors (21). The accumulation of MCs in cancer tissue can have dual effects, as it can be either beneficial or detrimental for the development of tumors.

These cells are present in brain tissue and can generate neuroinflammation that promotes tumor growth (22). Chemokines recruit MCs into brain tumor tissue where they become activated and generate different cytokines such as IL-8, growth factors, and vascular endothelial growth factor (VEGF), chemical mediators such as histamine and heparin, and tryptase and chymase that support the formation of new blood vessels and mediate the production of metastases (21). At the same time, MCs can be detrimental for tumor cells by producing several cytokines, including IL-1, IL-4, IL-6, and TNF, which limit the growth of the tumor mass and the formation of metastasis (23).

CONCLUSIONS

The immune system plays an important role in the brain and in tumors of the CNS. After they are recruited by chemokines released in situ, immune cells release inflammatory cytokines that may be beneficial or detrimental to tumor growth and the formation of metastasis.

Current research has focused attention on the use of immunotherapies for treating cancer, including brain tumors. Chimeric antigen receptor (CAR) T-cell therapy utilizes reconstructed patient T-cells that express CAR proteins directed toward surface-exposed tumor-associated antigens (TAAs). The use of CAR T-cell therapy has shown promising results in hematologic cancer studies (24) and for lymphoma (25,26); however, more research is needed to discover the role for this therapy in brain tumors, and for its utilization in clinical practice.

Conflict of interest

The author declares that they have no conflict of interest.

REFERENCES

1. Balkwill F. Cancer and the chemokine network. Nature Reviews Cancer. 2004;4(7):540-550. doi:https://doi.org/10.1038/nrc1388
2. Wieder T, Braumüller H, Kneilling M, Pichler B, Röcken M. T cell-mediated help against tumors. Cell Cycle. 2008;7(19):2974-2977. doi:https://doi.org/10.4161/cc.7.19.6798
3. Ramesh G, MacLean AG, Philipp MT. Cytokines and Chemokines at the Crossroads of Neuroinflammation, Neurodegeneration, and Neuropathic Pain. Mediators of Inflammation. 2013;2013:1-20. doi:https://doi.org/10.1155/2013/480739
4. Wraith DC, Nicholson LB. The adaptive immune system in diseases of the central nervous system. Journal of Clinical Investigation. 2012;122(4):1172-1179. doi:https://doi.org/10.1172/jci58648
5. Hendry S, Farnsworth RH, Solomon B, Achen MG, Stacker SA, Fox SB. The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment. Frontiers in Immunology. 2016;7. doi:https://doi.org/10.3389/fimmu.2016.00621
6. Becker JC, Andersen MH, Schrama D, Thor Straten P. Immune-suppressive properties of the tumor microenvironment. Cancer immunology, immunotherapy: CII. 2013;62(7):1137-1148. doi:https://doi.org/10.1007/s00262-013-1434-6
7. Kim YW, Jan KM, Jung DH, Cho MY, Kim NK. Histological inflammatory cell infiltration is associated with the number of lymph nodes retrieved in colorectal cancer. Anticancer Research. 2013;33(11):5143-5150.
8. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences. 2014;69 Suppl 1(1):S4-9. doi:https://doi.org/10.1093/gerona/glu057
9. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860-867. doi:https://doi.org/10.1038/nature01322
10. Walker PR, Prins RM, Dietrich PY, Liau LM. Harnessing T-Cell Immunity to Target Brain Tumors. Humana Press eBooks. Published online January 1, 2009:1165-1217. doi:https://doi.org/10.1007/978-1-60327-553-8_48
11. Carvalho da Fonseca AC, Badie B. Microglia and Macrophages in Malignant Gliomas: Recent Discoveries and Implications for Promising Therapies. Clinical and Developmental Immunology. 2013;2013:1-5. doi:https://doi.org/10.1155/2013/264124
12. Maugeri R, Schiera G, Di Liegro C, Fricano A, Iacopino D, Di Liegro I. Aquaporins and Brain Tumors. International Journal of Molecular Sciences. 2016;17(7):1029. doi:https://doi.org/10.3390/ijms17071029
13. Benitez-Rosario MA, McDarby G, Doyle R, Fabby C. Chronic Cluster-Like Headache Secondary to Prolactinoma: Uncommon Cephalalgia in Association with Brain Tumors. Journal of Pain and Symptom Management. 2009;37(2):271-276. doi:https://doi.org/10.1016/j.jpainsymman.2008.02.013
14. Horowitz HW. Fever of Unknown Origin or Fever of Too Many Origins? New England Journal of Medicine. 2013;368(3):197-199. doi:https://doi.org/10.1056/nejmp1212725
15. Skapenko A, Leipe J, Lipsky PE, Schulze-Koops H. The Role of the T Cell in Autoimmune Inflammation. Arthritis Research & Therapy. 2005;7(Suppl 2):S4. doi:https://doi.org/10.1186/ar1703
16. Albulescu R, Codrici E, Popescu ID, et al. Cytokine Patterns in Brain Tumour Progression. Mediators of Inflammation. 2013;2013. doi:https://doi.org/10.1155/2013/979748
17. Ott LW, Resing KA, Sizemore AW, et al. Tumor Necrosis Factor-α -and Interleukin-1-Induced Cellular Responses: Coupling Proteomic and Genomic Information. Journal of proteome research. 2007;6(6):2176-2185. doi:https://doi.org/10.1021/pr060665l
18. Jia X, Feng G, Wang Z, et al. Activation of mesenchymal stem cells by macrophages promotes tumor progression through immune suppressive effects. Oncotarget. 2016;7(15):20934-20944. doi:https://doi.org/10.18632/oncotarget.8064
19. Horuk R. Chemokine receptors. Cytokine & Growth Factor Reviews. 2001;12(4):313-335. doi:https://doi.org/10.1016/s1359-6101(01)00014-4
20. Vanderbilt JN, Mager EM, Allen L, et al. CXC Chemokines and Their Receptors Are Expressed in Type II Cells and Upregulated following Lung Injury. American Journal of Respiratory Cell and Molecular Biology. 2003;29(6):661-668. doi:https://doi.org/10.1165/rcmb.2002-0227oc
21. Krystel-Whittemore M, Dileepan KN, Wood JG. Mast Cell: a Multi-Functional Master Cell. Frontiers in Immunology. 2016;6. doi:https://doi.org/10.3389/fimmu.2015.00620
22. Ribatti D, Crivellato E. Mast cells, angiogenesis, and tumour growth. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. 2012;1822(1):2-8. doi:https://doi.org/10.1016/j.bbadis.2010.11.010
23. Theoharides TC, Conti P. Mast cells: the JEKYLL and HYDE of tumor growth. Trends in Immunology. 2004;25(5):235-241. doi:https://doi.org/10.1016/j.it.2004.02.013
24. Gill S, Maus MV, Porter DL. Chimeric antigen receptor T cell therapy: 25years in the making. Blood Reviews. 2016;30(3):157-167. doi:https://doi.org/10.1016/j.blre.2015.10.003
25. Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor–transduced T cells. Blood. 2012;119(12):2709-2720. doi:https://doi.org/10.1182/blood-2011-10-384388
26. Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Science Translational Medicine. 2016;8(355):355ra116. doi:https://doi.org/10.1126/scitranslmed.aaf8621