Cancer Stem Cell Vaccination Confers Significant Antitumor Immunity

Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
Cancer Research (Impact Factor: 9.33). 04/2012; 72(7):1853-64. DOI: 10.1158/0008-5472.CAN-11-1400
Source: PubMed


Most studies of cancer stem cells (CSC) involve the inoculation of cells from human tumors into immunosuppressed mice, preventing an assessment on the immunologic interactions and effects of CSCs. In this study, we examined the vaccination effects produced by CSC-enriched populations from histologically distinct murine tumors after their inoculation into different syngeneic immunocompetent hosts. Enriched CSCs were immunogenic and more effective as an antigen source than unselected tumor cells in inducing protective antitumor immunity. Immune sera from CSC-vaccinated hosts contained high levels of IgG which bound to CSCs, resulting in CSC lysis in the presence of complement. CTLs generated from peripheral blood mononuclear cells or splenocytes harvested from CSC-vaccinated hosts were capable of killing CSCs in vitro. Mechanistic investigations established that CSC-primed antibodies and T cells were capable of selective targeting CSCs and conferring antitumor immunity. Together, these proof-of-concept results provide a rationale for a new type of cancer immunotherapy based on the development of CSC vaccines that can specifically target CSCs.

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Available from: Mark E P Prince, Dec 30, 2013
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    • "Indeed, the relative immunogenicity of CSCs makes them a potential target for vaccination based cancer immunotherapy. With this regard, in a recent study of vaccination of mice with dendritic cells pulsed with syngeneic CSC lysate as TAAs, an effective therapeutic and immunological (both antibody and T cell-mediated) reaction has been acquired (Ning et al. 2012). Further, given that characterization of CSCs depends on their expression of ALDH, it is possible to generate anti-ALDH-specific CTLs with a therapeutic activity against human CSCs when xenografted into severe combined immunodeficiency (SCID) mice (Visus et al. 2011). "
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    ABSTRACT: Cancer stem cells (CSCs) need to survive cancer treatments with a specific end goal to provide new, more differentiated, metastatic-prone cancerous cells. This happens through diverse signals delivered within the tumor microenvironment where ample evidence indicates that altered developmental signaling pathways play an essential role in maintaining CSCs and accordingly the survival and the progression of the tumor itself. This review summarizes findings on the immunobiological properties of CSCs as compared with cancerous non-stem cells involving the expression of immunological molecules, cytokines and tumor antigens as well as the roles of the Notch, Wnt and Hedgehog pathways in the brain, breast and colon CSCs. We concluded that if CSCs are the main driving force behind tumor support and growth then understanding the molecular mechanisms and the immunological properties directing these cells for immune tolerance is of great clinical significance. Such knowledge will contribute to designing better targeted therapies that could prevent tumor recurrence and accordingly significantly improve cancer treatments and patient survival.
    Cytotechnology 12/2014; 67(5). DOI:10.1007/s10616-014-9830-0 · 1.75 Impact Factor
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    • "In ovarian SK-OV-3 cells, γδ T cells efficiently killed ovarian CSCs through IL-17 production [10]. Immune sera and CTLs from CSC-vaccinated hosts were capable of selective targeting CSCs and conferring antitumor immunity in murine melanoma and squamous cell tumors [11]. These results suggest that CSCs can be targeted by immune cells. "
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    ABSTRACT: In the present study, we investigated whether celecoxib could induce the expression of NKG2D ligands in clonogenic colon cancer cells, and increase their susceptibility to NK cell-mediated cell death. Celecoxib and its non-coxib analogue, 2,5-dimethyl celecoxib, induced ULBP-1 and DR5 in both COX-2 negative HCT-15 cells and COX-2 positive HT-29 cells. Celecoxib increased their susceptibility to NK92 cells in both DELFIA assay and soft agar colony forming assay. The inducibility of ULBP-1 and DR5 by celecoxib was not different between CD44- and CD44+ HCT-15 cells, and CD133- and CD133+ HT-29 cells. Celecoxib increased the susceptibility of highly clonogenic CD44+ HCT-15 and CD133+ HT-29 cells to NK92 cells, at least comparable to less clonogenic CD44- HCT-15 and CD133- HT-29 cells, respectively. In addition, celecoxib induced CHOP, and thapsigargin, an inducer of ER (endoplasmic reticulum) stress, induced DR5 but not ULBP1 in HCT-15. Taken together, these findings suggest that celecoxib induces the expression of ULBP-1 as well as DR5 in clonogenic colon cancer cells via COX-2 and ER stress-independent pathways, and increases their susceptibility to NK cells.
    Experimental Cell Research 09/2014; 330(2). DOI:10.1016/j.yexcr.2014.09.008 · 3.25 Impact Factor
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    • "Compared to the traditional whole tumor cell lysate-pulsed dendritic cell vaccine, the CSC lysate-pulsed dendritic cell vaccine exerts a more effective anti-tumor immunity [23]. Thus, in our research, we used the ALDHhigh H460 CSCs as an antigen source to pulse the dendritic cells and generate CSC-based dendritic cells. "
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    ABSTRACT: Background Currently, many studies suggest that cancer stem cells (CSCs) are responsible for tumor initiation, tumorigenesis, metastasis and recurrence. CSCs have been identified from various human and murine tumors. The identification of CSCs allows us to develop strategies to target the CSCs. Methods and Results In this study, we used ALDEFLUOR as a single marker to isolate the CSCs from the human lung cancer cell line H460. We then characterized the CSCs by testing their sphere formation ability and tumorigenicity. Furthermore, we used CSC lysate-pulsed dendritic cells to stimulate CD8+T cells as a treatment strategy. Our study demonstrated that ALDEFLUOR could be used as a single marker to identify CSCs from the human lung cancer cell line H460. The ALDHhigh cells could form more spheres and were more tumorigenic than the ALDHlow cells. Further study demonstrated that ALDHhigh-CD8+T cells conferred more significant antitumor effects, resulting in the inhibition of tumor growth and prolonged survival. And the ALDHhigh-CD8+T cells-mediated anti-tumor immunity might be due to the directly targeting against ALDHhigh cancer stem cells (CSCs). Conclusions This study shows that ALDHhigh-CD8+T cells mediate anti-tumor immunity by selectively targeting cancer stem cells, which result in inhibiting tumor growth and prolonging the survival of tumor-bearing mice, which provides a new strategy using ALDHhigh-CD8+T cells to treat tumors.
    PLoS ONE 08/2014; 9(8):e103193. DOI:10.1371/journal.pone.0103193 · 3.23 Impact Factor
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