Trends in Immunology
Volume 29, Issue 10, October 2008, Pages 464-468
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Cancer stem cells, CD200 and immunoevasion

https://doi.org/10.1016/j.it.2008.07.005Get rights and content

The limited success seen in cancer immunotherapy signifies that an alternative approach is required. Advances in cancer biology have identified a biologically unique subpopulation of cells, termed cancer stem cells (CSC), that survive after conventional therapy. CSCs are the putative cancer-initiating cells responsible for tumor initiation, progression and metastasis. CSCs might be able to evade the immune system by generating a tolerogenic response facilitated by the immunosuppressive factor CD200. This article reviews the biological importance of CSCs and the potentially important role of CD200 in tumor immunology. Moreover, we discuss the prospective role CD200 plays in the ability of a CSC to escape the immune system. Future immunotherapy must consider targeting CSCs to achieve curative responses.

Section snippets

Overlooking cancer stem cells

One of the challenges in developing viable immune-based therapy of cancer is the impact a tumor and the tumor microenvironment plays in suppressing the immune system. A tremendous amount of progress has been made in evaluating the mechanisms by which a tumor is able to avoid and/or suppress immune detection. Despite these advances, tumor immunotherapy has struggled to develop effective applications; therefore, new approaches and paradigms are required to develop future treatments.

Vaccines were

Introduction to CSCs

Tumors are composed of a heterogeneous population of cells that include highly differentiated cells, transit-amplifying cells and the quiescent CSCs (Figure 1) [5]. The oncogenic force behind tumor formation and recurrence comes from the rare population of CSCs that reside in the tumor, and these cells give rise to the other more differentiated cells in the tumor [6]. The more differentiated progenitor cells have far less proliferative potential and limited tumorigenic capabilities [7]. The

CSCs and patient prognosis

It has been shown that CSCs are markers for poor patient prognosis [11]. Microarray profiling of putative breast CSCs revealed an ‘invasiveness’ gene signature (IGS) that was associated with overall survival and metastasis-free survival in breast cancer patients [12]. The IGS was also a prognostic indicator in lung cancer, medulloblastoma and prostate cancer [12]. In another study, certain brain CSCs were particularly resistant to radiotherapy [13]. Glioma CSCs (CD133-expressing cells) were

CSCs and immune evasion

A hallmark of tumor progression and recurrence is the ability to evade the immune system, and CSCs might play an important role in this ability. However, it is unknown whether CSCs are even recognized by the immune system, because most tumor immunology models are based on whole tumor cell populations or antigens characterized from the ‘bulk’ tumor. Tumor tolerance is the ability of a tumor to escape recognition by the immune system, thereby allowing transformed cells to grow out [15]. CSCs

The role of CD200 in normal immune responses

CD200 is a highly conserved member of the immunoglobulin superfamily and is commonly expressed in cells of the myeloid lineage such as macrophages, dendritic cells, neutrophils, mast cells and eosinophils. However, its expression is not limited to these cell types, and it is also found on B cells, activated T cells, endothelial neuronal cells and cells in the reproductive organs 18, 19, 20, 21. Expression of CD200's cognate receptor (CD200R), however, is limited to the myeloid lineages and

CD200's prognostic capability in cancer

CD200 expression has been found in several cancer cell lines and/or tissues, including ovarian, melanoma, head and neck carcinoma, testicular, malignant mesothelioma, neuroblastoma, renal cell carcinoma, chronic lymphocytic leukemia, prostate, breast and colon cancers 31, 32, 33. Interestingly, CD200 is implicated as a prognostic factor in multiple myeloma (MM) and acute myeloid leukemia (AML) 34, 35. For MM and AML, cDNA microarrays were analyzed from patient samples and CD200 was expressed in

CD200 and its role in tumor immunity

The first study to demonstrate a role for CD200 in tumor immunity was done using two models of immune protection from tumor growth [36]. The first model was a bone marrow transplant (BMT) model that induces a graft versus leukemia response. C57BL/6 mice were given an allogenic bone marrow transplant followed by injection with leukemic cells. The result was a higher tumor rejection rate in the allogenic BMT compared with the syngeneic BMT. The second model preimmunized C57BL/6 with leukemic

CD200 and its potential in cancer immunotherapy

CD200 was first identified as a viable therapeutic option in B-cell chronic lymphocyte leukemia (CLL) [40]. CD200 was overexpressed 1.6- to 5.4-fold in leukemic cells from CLL patients [40]. The addition of CD200+ CLL cells to mixed lymphocyte reactions manifested an immunological shift from a Th1-like response to a Th2-like response., The addition of a blocking chimeric CD200 antibody to the cultures restored Th1 responses [40]. The therapeutic potential of CD200 was subsequently tested in an

CD200 as a marker for normal and cancer stem cells

In addition to being an immunosuppressive protein, CD200 is also a marker of human hair follicle bulge stem cells [41]. The hair follicle is a constant self-renewing structure that contains a ‘bulge’ area rich in multipotent stem cells that support the cycling hair cell. Bulge cells are located in the outer route sheath (ORS), a structure that surrounds the hair shaft [41]. Gene transcripts isolated from bulge stem cells identified CD200 and several genes associated with the stem cell signaling

CSCs and CD200 define a new model of tumor immunity

The identification of CD200 as a stem cell marker, a prognostic factor in cancer and an attenuator of tumor immunity suggests this protein might play a role in CSC function. CD200's effect on attenuating tumor immunity suggests its role might be tied to a CSC's ability to escape the immune system (see Figure 2). Expression of CD200 on a CSC would presumably induce downregulation of a Th1 immune response, an important mediator of anti-tumor responses 42, 43, 44. This alteration in immune

Future directions for cancer stem cells and immunotherapy

The recent paradigm shift and discovery of CSCs has caused considerable re-evaluation concerning the oncogenesis and development of cancers. The findings that CSCs might be chemo- and radiation-resistant, and now suggested to have immunosuppressive functions, portend an ominous challenge to future therapies. Although some targeting of stem cell molecular pathways, such as Hedgehog, Notch, and β-catenin have been initiated (with specific agents such as cyclopamine and γ-secretase inhibitors),

Conflict of interest statement

The corresponding authors have no conflict of interest to report.

Acknowledgements

The authors thank Elaine Hurt for wonderful editing assistance. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This work has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400. The content of this paper does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of

References (47)

  • S.A. Rosenberg

    Cancer immunotherapy: moving beyond current vaccines

    Nat. Med.

    (2004)
  • T.F. Gajewski

    Immune resistance orchestrated by the tumor microenvironment

    Immunol. Rev.

    (2006)
  • B.T. Kvinlaug et al.

    Targeting cancer stem cells

    Expert Opin. Ther. Targets

    (2007)
  • D.G. Tang

    Prostate cancer stem/progenitor cells: identification, characterization, and implications

    Mol. Carcinog.

    (2007)
  • R. Pardal

    Applying the principles of stem-cell biology to cancer

    Nat. Rev. Cancer

    (2003)
  • T. Lapidot

    A cell initiating human acute myeloid leukaemia after transplantation into SCID mice

    Nature

    (1994)
  • M. Al-Hajj

    Cancer stem cells and oncology therapeutics

    Curr. Opin. Oncol.

    (2007)
  • C. Li

    Identification of pancreatic cancer stem cells

    Cancer Res.

    (2007)
  • R. Liu

    The prognostic role of a gene signature from tumorigenic breast-cancer cells

    N. Engl. J. Med.

    (2007)
  • S. Bao

    Glioma stem cells promote radioresistance by preferential activation of the DNA damage response

    Nature

    (2006)
  • F. Zeppernick

    Stem cell marker CD133 affects clinical outcome in glioma patients

    Clin. Cancer Res.

    (2008)
  • W. Zou

    Immunosuppressive networks in the tumour environment and their therapeutic relevance

    Nat. Rev. Cancer

    (2005)
  • C. Nathan et al.

    Putting the brakes on innate immunity: a regulatory role for CD200?

    Nat. Immunol.

    (2001)
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