Skip to main content
SpringerLink
Log in

Susceptibility to cytotoxic T cell lysis of cancer stem cells derived from cervical and head and neck tumor cell lines

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

To explore cancer stem cell susceptibility to a host’s cytotoxic T lymphocyte (CTL)-mediated immune response.

Methods

We compared the susceptibility of putative CSC generated from cancer cell lines to immunologic recognition and killing by alloantigen-specific CD8+ CTL. CSC-enriched spheroid culture-derived cells (SDC) exhibited higher expression of ALDH, ICAM1 and of stem/progenitor cell markers on all 3 tumor cell lines investigated and lower MHC class I on the cervical cancer cell line as compared to their monolayer-derived cells (MDC).

Results

The expression of ICAM1 and MHCI was upregulated by IFN-γ treatment. CSC populations were less sensitive to MHC class I-restricted alloantigen-specific CD8+ CTL lysis as compared to matched MDC. IFN-γ pretreatment resulted in over-proportionally enhanced lysis of SDC. Finally, the subset of ALDHhigh expressing SDC presented more sensitivity toward CD8+ CTL killing than the ALDHlow SDC.

Conclusions

Tumor therapy resistance has been attributed to cancer stem cells (CSC). We show in vitro susceptibility of CSC to CTL-mediated lysis. Immunotherapy targeting of ALDH+ CSC may therefore be a promising approach. Our results and method may be helpful for the development and optimization of adjuvants, as here exemplified for INF-γ, for CSC-targeted vaccines, independent of the availability of CSC-specific antigens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Albers A, Abe K, Hunt J, Wang J, Lopez-Albaitero A, Schaefer C, Gooding W, Whiteside TL, Ferrone S, DeLeo A, Ferris RL (2005) Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck. Cancer Res 65(23):11146–11155. doi:10.1158/0008-5472.CAN-05-0772

    Article  PubMed  CAS  Google Scholar 

  • Albers AE, Strauss L, Liao T, Hoffmann TK, Kaufmann AM (2011) T cell-tumor interaction directs the development of immunotherapies in head and neck cancer. Clin Dev Immunol 2010:236378. doi:10.1155/2010/236378

    Google Scholar 

  • Andratschke M, Pauli C, Stein M, Chaubal S, Wollenberg B (2003) MHC-class I antigen expression on micrometastases in bone marrow of patients with head and neck squamous cell cancer. Anticancer Res 23(2B):1467–1471

    PubMed  CAS  Google Scholar 

  • Bortolomai I, Canevari S, Facetti I, De Cecco L, Castellano G, Zacchetti A, Alison MR, Miotti S (2010) Tumor initiating cells: development and critical characterization of a model derived from the A431 carcinoma cell line forming spheres in suspension. Cell Cycle 9(6):1194–1206

    Article  PubMed  CAS  Google Scholar 

  • Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122(6):947–956. doi:10.1016/j.cell.2005.08.020

    Article  PubMed  CAS  Google Scholar 

  • Brown CE, Starr R, Martinez C, Aguilar B, D’Apuzzo M, Todorov I, Shih CC, Badie B, Hudecek M, Riddell SR, Jensen MC (2009) Recognition and killing of brain tumor stem-like initiating cells by CD8 + cytolytic T cells. Cancer Res 69(23):8886–8893. doi:10.1158/0008-5472.CAN-09-2687

    Article  PubMed  CAS  Google Scholar 

  • Castriconi R, Daga A, Dondero A, Zona G, Poliani PL, Melotti A, Griffero F, Marubbi D, Spaziante R, Bellora F, Moretta L, Moretta A, Corte G, Bottino C (2009) NK cells recognize and kill human glioblastoma cells with stem cell-like properties. J Immunol 182(6):3530–3539. doi:10.4049/jimmunol.0802845

    Article  PubMed  CAS  Google Scholar 

  • Chen YC, Chen YW, Hsu HS, Tseng LM, Huang PI, Lu KH, Chen DT, Tai LK, Yung MC, Chang SC, Ku HH, Chiou SH, Lo WL (2009) Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem Biophys Res Commun 385(3):307–313. doi:10.1016/j.bbrc.2009.05.048

    Article  PubMed  CAS  Google Scholar 

  • Chen C, Wei Y, Hummel M, Hoffmann TK, Gross M, Kaufmann AM, Albers AE (2011) Evidence for epithelial-mesenchymal transition in cancer stem cells of head and neck squamous cell carcinoma. PLoS ONE 6(1):e16466. doi:10.1371/journal.pone.0016466

    Article  PubMed  CAS  Google Scholar 

  • Clay MR, Tabor M, Owen JH, Carey TE, Bradford CR, Wolf GT, Wicha MS, Prince ME (2010) Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck 32(9):1195–1201. doi:10.1002/hed.21315

    Article  PubMed  Google Scholar 

  • Evans M, Borysiewicz LK, Evans AS, Rowe M, Jones M, Gileadi U, Cerundolo V, Man S (2001) Antigen processing defects in cervical carcinomas limit the presentation of a CTL epitope from human papillomavirus 16 E6. J Immunol 167(9):5420–5428

    PubMed  CAS  Google Scholar 

  • Garcia-Hernandez Mde L, Gray A, Hubby B, Klinger OJ, Kast WM (2008) Prostate stem cell antigen vaccination induces a long-term protective immune response against prostate cancer in the absence of autoimmunity. Cancer Res 68(3):861–869. doi:10.1158/0008-5472.CAN-07-0445

    Article  PubMed  Google Scholar 

  • Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567. doi:10.1016/j.stem.2007.08.014

    Article  PubMed  CAS  Google Scholar 

  • Hoffmann TK, Sonkoly E, Hauser U, van Lierop A, Whiteside TL, Klussmann JP, Hafner D, Schuler P, Friebe-Hoffmann U, Scheckenbach K, Erjala K, Grenman R, Schipper J, Bier H, Balz V (2008) Alterations in the p53 pathway and their association with radio- and chemosensitivity in head and neck squamous cell carcinoma. Oral Oncol 44(12):1100–1109. doi:10.1016/j.oraloncology.2008.02.006

    Article  PubMed  CAS  Google Scholar 

  • Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H, Fields JZ, Wicha MS, Boman BM (2009) Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res 69(8):3382–3389. doi:10.1158/0008-5472.CAN-08-4418

    Article  PubMed  CAS  Google Scholar 

  • Jiang F, Qiu Q, Khanna A, Todd NW, Deepak J, Xing L, Wang H, Liu Z, Su Y, Stass SA, Katz RL (2009) Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res 7(3):330–338. doi:10.1158/1541-7786.MCR-08-0393

    Article  PubMed  CAS  Google Scholar 

  • Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, Wong KY, Sung KW, Lee CW, Zhao XD, Chiu KP, Lipovich L, Kuznetsov VA, Robson P, Stanton LW, Wei CL, Ruan Y, Lim B, Ng HH (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38(4):431–440. doi:10.1038/ng1760

    Article  PubMed  CAS  Google Scholar 

  • Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, Guan XY (2008) Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res 6(7):1146–1153. doi:10.1158/1541-7786.MCR-08-0035

    Article  PubMed  CAS  Google Scholar 

  • Mehta AM, Jordanova ES, Kenter GG, Ferrone S, Fleuren GJ (2008) Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma. Cancer Immunol Immunother 57(2):197–206. doi:10.1007/s00262-007-0362-8

    Article  PubMed  CAS  Google Scholar 

  • Meissner M, Reichert TE, Kunkel M, Gooding W, Whiteside TL, Ferrone S, Seliger B (2005) Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res 11(7):2552–2560. doi:10.1158/1078-0432.CCR-04-2146

    Article  PubMed  CAS  Google Scholar 

  • Okamoto A, Chikamatsu K, Sakakura K, Hatsushika K, Takahashi G, Masuyama K (2009) Expansion and characterization of cancer stem-like cells in squamous cell carcinoma of the head and neck. Oral Oncol 45(7):633–639. doi:10.1016/j.oraloncology.2008.10.003

    Article  PubMed  CAS  Google Scholar 

  • Pellegatta S, Poliani PL, Corno D, Menghi F, Ghielmetti F, Suarez-Merino B, Caldera V, Nava S, Ravanini M, Facchetti F, Bruzzone MG, Finocchiaro G (2006) Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Res 66(21):10247–10252. doi:10.1158/0008-5472.CAN-06-2048

    Article  PubMed  CAS  Google Scholar 

  • Prasmickaite L, Engesaeter BO, Skrbo N, Hellenes T, Kristian A, Oliver NK, Suo Z, Maelandsmo GM (2010) Aldehyde dehydrogenase (ALDH) activity does not select for cells with enhanced aggressive properties in malignant melanoma. PLoS ONE 5(5):e10731. doi:10.1371/journal.pone.0010731

    Article  PubMed  Google Scholar 

  • Stanke J, Hoffmann C, Erben U, von Keyserling H, Stevanovic S, Cichon G, Schneider A, Kaufmann AM (2010) A flow cytometry-based assay to assess minute frequencies of CD8 + T cells by their cytolytic function. J Immunol Methods 360(1–2):56–65. doi:10.1016/j.jim.2010.06.005

    Article  PubMed  CAS  Google Scholar 

  • Street D, Kaufmann AM, Vaughan A, Fisher SG, Hunter M, Schreckenberger C, Potkul RK, Gissmann L, Qiao L (1997) Interferon-gamma enhances susceptibility of cervical cancer cells to lysis by tumor-specific cytotoxic T cells. Gynecol Oncol 65(2):265–272. doi:10.1006/gyno.1997.4667

    Article  PubMed  CAS  Google Scholar 

  • Todaro M, Lombardo Y, Stassi G (2010) Evidences of cervical cancer stem cells derived from established cell lines. Cell Cycle 9(7):1238–1239

    Article  PubMed  CAS  Google Scholar 

  • Visus C, Ito D, Amoscato A, Maciejewska-Franczak M, Abdelsalem A, Dhir R, Shin DM, Donnenberg VS, Whiteside TL, DeLeo AB (2007) Identification of human aldehyde dehydrogenase 1 family member A1 as a novel CD8 + T-cell-defined tumor antigen in squamous cell carcinoma of the head and neck. Cancer Res 67(21):10538–10545. doi:10.1158/0008-5472.CAN-07-1346

    Article  PubMed  CAS  Google Scholar 

  • Visus C, Wang Y, Lozano-Leon A, Ferris RL, Silver S, Szczepanski MJ, Brand RE, Ferrone CR, Whiteside TL, Ferrone S, DeLeo AB, Wang X (2011) Targeting ALDH(bright) human carcinoma-initiating cells with ALDH1A1-specific CD8(+) T cells. Clin Cancer Res 17(19):6174–6184. doi:10.1158/1078-0432.CCR-11-1111

    Article  PubMed  CAS  Google Scholar 

  • Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8(10):755–768. doi:10.1038/nrc2499

    Article  PubMed  CAS  Google Scholar 

  • Wollenberg B, Zeidler R, Lebeau A, Mack B, Lang S (1998) Lack of B7.1 and B7.2 on head and neck cancer cells and possible significance for gene therapy. Int J Mol Med 2(2):167–171

    PubMed  CAS  Google Scholar 

  • Wu A, Wiesner S, Xiao J, Ericson K, Chen W, Hall WA, Low WC, Ohlfest JR (2007) Expression of MHC I and NK ligands on human CD133 + glioma cells: possible targets of immunotherapy. J Neurooncol 83(2):121–131. doi:10.1007/s11060-006-9265-3

    Article  PubMed  CAS  Google Scholar 

  • Xu Q, Liu G, Yuan X, Xu M, Wang H, Ji J, Konda B, Black KL, Yu JS (2009) Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens. Stem Cells 27(8):1734–1740. doi:10.1002/stem.102

    Article  PubMed  CAS  Google Scholar 

  • Yoshida A (1992) Molecular genetics of human aldehyde dehydrogenase. Pharmacogenetics 2(4):139–147

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

L. L. Lanier for the gift of eukaryotic expression plasmid pBJ.

Conflict of interest

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Clinic for Gynecology, Charité-Universitätsmedizin Berlin, 12200, Berlin, Germany

    Tian Liao, Andreas M. Kaufmann, Voramon Sangvatanakul & Tina Kube

  2. Department of Otolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Tian Liao, Xu Qian, Chao Chen & Andreas E. Albers

  3. Department of Hand and Plastic Surgery, The Second Affiliated Hospital of Wenzhou Medical College, Xueyuan West Road 109#, Wenzhou, 325027, Zhejiang Province, China

    Guoyou Zhang

Authors
  1. Tian Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas M. Kaufmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xu Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Voramon Sangvatanakul
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tina Kube
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guoyou Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andreas E. Albers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas E. Albers.

Additional information

Tian Liao and Andreas M. Kaufmann contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 486 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liao, T., Kaufmann, A.M., Qian, X. et al. Susceptibility to cytotoxic T cell lysis of cancer stem cells derived from cervical and head and neck tumor cell lines. J Cancer Res Clin Oncol 139, 159–170 (2013). https://doi.org/10.1007/s00432-012-1311-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-012-1311-2

Keywords

Search

Navigation