Cancer-initiating cells that launch glioblastoma multiforme, the most
lethal type of brain tumor, also suppress an immune system attack on
the disease, scientists from The University of Texas M. D. Anderson
Cancer Center report in a paper featured on the cover of the Jan. 15
issue of Clinical Cancer Research.(1)

Glioblastoma Muliforme
Glioblastoma multiforme (GBM) is the most common and most aggressive of the primary brain tumors. It responds poorly to therapy and glioblastoma multiforme cancer-initiating cellshave been shown to mediate resistance to both chemotherapy and radiation. The current World Health Organization (WHO) classification of primary brain tumors lists GBM as a grade IV astrocytoma.Astrocytomas,which originate in star-shaped brain cells called astrocytes, are one of the 3 distinct types of gliomas(tumors that arise in the brain or spinal cord) in the brain,although mixed cell types occur as well. GBMs are highly malignant,infiltrate the brain extensively, and at times may become enormous before producing symptoms(1,2)

Image via wikipedia:Two images - one showing a normal PET scan, the other showing astrocytoma
Research
The researchers demonstrate that the cancer initiating stem cells stifle the
 immune response in a variety of ways, but that the effect can be
greatly diminished by encouraging the stem cells to differentiate into
other types of brain cell.

"We've known for years that
glioblastoma and cancer patients in general have impaired immune
responses," said senior author Amy Heimberger, M.D., an associate professor in M. D. Anderson's Department of Neurosurgery. "Our research uncovers an important mechanism that shows how that happens. The cancer
stem cells inhibit T cell response, and it is these T cells that recognize and eradicate cancer." (3)

Definition of Cancer Stem Cells
Definitions of cancer stem cells vary. To meet the researchers' definition, the cells had to express a marker called CD133, formneurospheres (free floating structures that look like little round balls) in culture, and be able to recreate glioblastoma multiforme when injected into the
brain of a mouse. They also had to be capable of differentiating into specific types of brain cells -- neurons, astrocytes and glial cells.(1,3)

Suppression of T cell response
Wei explained that the glioblastoma stem cells suppress T cell response three different ways by:

  • Producing immunosuppressive cytokines that prevent the responses of T cells.



  • Inducing some T cells to become regulatory T cells, which act as brakes on the immune response.



  • Killing T cells via apoptosis, or programmed cell suicide.
    This is accomplished via the immunosuppressive protein B7-H1 in the stem cells directly
    contacting the T cells or by secretion of Galectin-3.(3)

Wei said this immunosuppressive effect was reversed when the team placed the undifferentiated glioma stem cells in a culture medium that causes them to differentiate into the three types of neural cell.(3)

"There are multiple research groups around the country, including ours, trying
to develop vaccines or other immunotherapeutics against glioma stem cells," Heimberger said. "Now we have to be cognizant that the stem cell may deliver a fatal blow back to the immune system, which will help us understand how to design immune-based therapies." (3)

Conclusions of the Research

The conclusion of the research was that the cancer-initiating stem cells
contribute to tumor evasion of the immunosurveillance and that approaches that alter the differentiation state may have immunotherapeutic potential.New drugs or combination therapies are needed, because after decades of research, little progress has been made in treating glioblastoma multiforme. With the best of care patients survive an average of 14 months.(1,3)

B7-H1

B7-H1 is also known as CD274 (Cluster of Diffrentiation 274) and PD-L1 (Programmed Death Ligand) and is expressed on the surface of cells such as macrophages.Macrophages are white blood cells that phagocytose (engulf and digest) infectous agents and cellular debris and also
influence another set of white blood cells called lymophyctes ,which include T-cells,B cells and Natural killer cells, to respond to these threats.It is also expressed on t-cells,Natural killer cells,myleoid DCs,B cells, epithelial cells, and vascular endothelial cells upon activation of Interferon-γ . (4,5,6,7)

Galectin-3
Galectin-3(formerly called Mac- 2 antigen) is a ∼30 kDa carbohydrate-binding protein that
is a  member of large family of β-galactoside–binding animal lectins. It is secreted by various cell types including monocytes, macrophages and epithelial cells and has been associated with the inhibition ofapoptosis through Bcl-2 and the progression of cancer as well as being a mediator of inflammation.(8,9,10,11) Galectin-3 has also been shown to  regulate such fundamental cellular processes as pre-mRNA  splicing and has been found to stimulate the DNA-binding activity of a
transcriptional factor,  TTF-1.Galectin-3 expression is dysregulated upon transformation of normal cells to tumor cells and it has been shown that the presence of galectin-3 in transformed cells can promote an invasive phenotype.(12)

STAT3 pathway Inhibits T cell Response

In another separate paper in the Jan. 15 issue of Molecular Cancer Therapeutics, the research team also reported that the STAT3 signaling pathway is highly active in glioblastoma stem cells and suppresses immune system response.Heimberger said the STAT3 molecule is known to induce cancer proliferation and survival migration and invasion, growth of new blood vessels, and immunosuppression.Inhibiting STAT3, either by silencing it with small interfering RNA or by treatment with an experimental drug called WP1066, reactivates the immune response.

The STAT-3 Molecule


Image:Stat3 Structure via wikipedia

STAT-3 or Signal transducer and activator of transcription 3 is as the name suggests a transcription factor that is encoded in humans by the STAT-3 gene.A transcription factor is a protein that binds to specific DNA sequences and controls the transcription or transfer of genetic
information from DNA to mRNA. STAT-3 is a member of the STAT protein family which contains transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines (substances secreted by specific immune cells which carry signals
locally between cells and thus have an effect on other cells) and growth factors, hence they act as signal transducers in the cytoplasm and transcription activators in the nucleus.In mammals, STATs comprise a family of seven structurally and functionally related proteins: Stat1, Stat2, Stat3, Stat4, Stat5a and Stat5b, Stat6. STAT proteins play a critical role in regulating innate and acquired host immune responses. Dysregulation of at least two STAT signalling cascades (i.e. Stat3 and Stat5) is associated with cellular transformation.(13)

Using STAT-3 inhibitor to restore cell function

"We showed that if you treat the cancer stem cells with an inhibitor of STAT3, you can restore T cell proliferation and the ability of those cells to make pro-inflammatory cytokines,"
Heimberger said.While the response is powerful it is not complete, so the researchers conclude
there a STAT3-independent pathway is also at work in mediating immune suppression.(3)

Research continues on how the inhibitors work, and whether they cause the stem cell differentiation that the team has shown reverses immune suppression.The experimental drug WP1066 was developed by Waldemar Priebe, Ph.D., professor in M. D. Anderson's Department of Experimental Therapeutics. The drug has been shown to inhibit STAT3 in mice and reverse the immune suppression caused by cancer stem cells.The research was funded by grants from the Anthony Bullock III Foundation, the Dr. Marnie Rose Foundation, M. D. Anderson
and the National Cancer Institute.(3)

References



  1. Source: Jun Wei, Jason Barr, Ling-Yuan Kong, Yongtao Wang, Adam Wu, Amit K. Sharma, Joy Gumin, Verlene Henry, Howard Colman, Raymond Sawaya, Frederick F. Lang, Amy B. Heimberger (2009)Glioma-associated Cancer-Initiating cells Induce Immunosuppression,Clinical Cancer Research ,Published OnlineFirst
    January 12, 2010;
    doi:10.1158/1078-0432.


  2. Glioblastoma Multiforme :http://emedicine.medscape.com/article/1156220-overview


  3. http://www.scienceblog.com/cms/cancer-stem-cells-suppress-immune-response-against-brain-tumor-29195.htmlFlies 


  4. DB, Chen L (April 2007). "The new B7s: playing a pivotal role in tumor immunity". J Immunother. 30 (3): 251–60. PMID 17414316


  5. Lee SJ, Jang BC, Lee SW, Yang YI, Suh SI, Park YM, Oh S, Shin JG, Yao S,
    Chen L, Choi IH. (February 2006). "Interferon regulatory factor-1 is
    prerequisite to the constitutive expression and IFN-gamma-induced
    upregulation of B7-H1 (CD274)". FEBS Lett. 580 (3): 755–62. PMID 16413538


  6. Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H,
    Pardoll DM, Okumura K, Azuma M, Yagita H (November 2002). "Expression
    of programmed death 1 ligands by murine T cells and APC.". J Immunol. 169 (10): 5538–45. PMID 12421930.


  7. Loke p,Alison JP (2003) "PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5336–41. doi:10.1073/pnas.0931259100. PMID 12697896.


  8. Critical Role of galetin-3 in phagocytosis by macrophages Volume
    112, Issue 3     (August 1,2003)J. Clin. Invest.
    112(3): 389-397 (2003). doi:10.1172/JCI17592.


  9. Nakamura,
    M. et al. Involvement of galectin-3 expression in colorectal cancer
    progression andmetastasis. Int. J. Oncol., 15, 143-148, (1999).


  10. Almkvist, J., and Karlsson, A., Galectins as inflammatory mediators. Glycoconj. J., 19, 575-81(2004).


  11. Macrophage surface glycoproteins binding to galectin-3 (Mac-2-antigen):http://www.springerlink.com/content/m243rg4626274630/


  12. http://web.mit.edu/glycomics/moleculepages/cbp/galectins/gal3_human


  13. http://www.ebi.ac.uk/interpro/DisplayIproEntry?ac=IPR001217






Further Reading


  • STAT family and pathway details on Interpro:http://www.ebi.ac.uk/interpro/DisplayIproEntry?ac=IPR001217


  • STAT 3 pathway:http://www.sabiosciences.com/pathway.php?sn=STAT3_Pathway


  • Galectin 3,Carbohydrate Binding Proteins database: http://web.mit.edu/glycomics/moleculepages/cbp/galectins/gal3_human/


  • Galectin 3 info:http://www.galectin-3.com/?page_id=17