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Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma

Abstract

Cancer immunoresistance and immune escape1,2,3 may play important roles in tumor progression and pose obstacles for immunotherapy. Expression of the immunosuppressive protein B7 homolog 1 (B7-H1), also known as programmed death ligand-1 (PD-L1), is increased in many pathological conditions, including cancer4,5,6,7,8,9,10. Here we show that expression of the gene encoding B7-H1 increases post transcriptionally in human glioma after loss of phosphatase and tensin homolog (PTEN) and activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway. Tumor specimens from individuals with glioblastoma multiforme (GBM) had levels of B7-H1 protein that correlated with PTEN loss, and tumor-specific T cells lysed human glioma targets expressing wild-type PTEN more effectively than those expressing mutant PTEN. These data identify a previously unrecognized mechanism linking loss of the tumor suppressor PTEN with immunoresistance, mediated in part by B7-H1.

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Figure 1: B7-H1 protein levels are elevated after Akt activation and PTEN dysfunction.
Figure 2: B7-H1 protein levels are regulated by PTEN and Akt activity.
Figure 3: Activation of Akt pathway upregulates B7-H1 expression through translational regulation.
Figure 4: Loss of PTEN function and upregulation of B7-H1 reduces cytotoxic T lymphocyte (CTL)-induced apoptosis.

References

  1. Dunn, G.P., Bruce, A.T., Ikeda, H., Old, L.J. & Schreiber, R.D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    Article  CAS  Google Scholar 

  2. Dunn, G.P., Old, L.J. & Schreiber, R.D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148 (2004).

    Article  CAS  Google Scholar 

  3. Dunn, G.P., Old, L.J. & Schreiber, R.D. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329–360 (2004).

    Article  CAS  Google Scholar 

  4. Blank, C., Gajewski, T.F. & Mackensen, A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol. Immunother. 54, 307–314 (2005).

    Article  CAS  Google Scholar 

  5. Blank, C. et al. Blockade of PD-L1 (B7–H1) augments human tumor-specific T cell responses in vitro. Int. J. Cancer 119, 317–327 (2006).

    Article  CAS  Google Scholar 

  6. Hirano, F. et al. Blockade of B7–H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 65, 1089–1096 (2005).

    CAS  PubMed  Google Scholar 

  7. Iwai, Y., Terawaki, S. & Honjo, T. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int. Immunol. 17, 133–144 (2005).

    Article  CAS  Google Scholar 

  8. Ohigashi, Y. et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin. Cancer Res. 11, 2947–2953 (2005).

    Article  CAS  Google Scholar 

  9. Saudemont, A. & Quesnel, B. In a model of tumor dormancy, long-term persistent leukemic cells have increased B7–H1 and B7.1 expression and resist CTL-mediated lysis. Blood 104, 2124–2133 (2004).

    Article  CAS  Google Scholar 

  10. Thompson, R.H. et al. B7–H1 glycoprotein blockade: a novel strategy to enhance immunotherapy in patients with renal cell carcinoma. Urology 66, 10–14 (2005).

    Article  Google Scholar 

  11. Pardoll, D. & Allison, J. Cancer immunotherapy: breaking the barriers to harvest the crop. Nat. Med. 10, 887–892 (2004).

    Article  CAS  Google Scholar 

  12. Dong, H., Zhu, G., Tamada, K. & Chen, L. B7–H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 5, 1365–1369 (1999).

    Article  CAS  Google Scholar 

  13. Dong, H. et al. Tumor-associated B7–H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).

    Article  CAS  Google Scholar 

  14. Dong, H. & Chen, L. B7–H1 pathway and its role in the evasion of tumor immunity. J. Mol. Med. 81, 281–287 (2003).

    Article  CAS  Google Scholar 

  15. Latchman, Y.E. et al. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc. Natl. Acad. Sci. USA 101, 10691–10696 (2004).

    Article  CAS  Google Scholar 

  16. Dong, H. et al. Costimulating aberrant T cell responses by B7–H1 autoantibodies in rheumatoid arthritis. J. Clin. Invest. 111, 363–370 (2003).

    Article  CAS  Google Scholar 

  17. Wintterle, S. et al. Expression of the B7-related molecule B7–H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res. 63, 7462–7467 (2003).

    CAS  Google Scholar 

  18. Mischel, P.S. et al. Identification of molecular subtypes of glioblastoma by gene expression profiling. Oncogene 22, 2361–2373 (2003).

    Article  CAS  Google Scholar 

  19. Vivanco, I. & Sawyers, C.L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501 (2002).

    Article  CAS  Google Scholar 

  20. Sulis, M.L. & Parsons, R. PTEN: from pathology to biology. Trends Cell Biol. 13, 478–483 (2003).

    Article  CAS  Google Scholar 

  21. Rajasekhar, V.K. et al. Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol. Cell 12, 889–901 (2003).

    Article  CAS  Google Scholar 

  22. Kahlon, K.S. et al. Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res. 64, 9160–9166 (2004).

    Article  CAS  Google Scholar 

  23. Rich, J.N. & Bigner, D.D. Development of novel targeted therapies in the treatment of malignant glioma. Nat. Rev. Drug Discov. 3, 430–446 (2004).

    Article  CAS  Google Scholar 

  24. Mischel, P.S., Cloughesy, T.F. & Nelson, S.F. DNA-microarray analysis of brain cancer: molecular classification for therapy. Nat. Rev. Neurosci. 5, 782–792 (2004).

    Article  CAS  Google Scholar 

  25. Blume-Jensen, P. & Hunter, T. Oncogenic kinase signalling. Nature 411, 355–365 (2001).

    Article  CAS  Google Scholar 

  26. Thompson, R.H. et al. Costimulatory B7–H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc. Natl. Acad. Sci. USA 101, 17174–17179 (2004).

    Article  CAS  Google Scholar 

  27. Wilmotte, R. et al. B7-homolog 1 expression by human glioma: a new mechanism of immune evasion. Neuroreport 16, 1081–1085 (2005).

    Article  CAS  Google Scholar 

  28. Kaur, S., Uddin, S. & Platanias, L.C. The PI3' kinase pathway in interferon signaling. J. Interferon Cytokine Res. 25, 780–787 (2005).

    Article  CAS  Google Scholar 

  29. Panner, A., James, C.D., Berger, M.S. & Pieper, R.O. mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme cells. Mol. Cell. Biol. 25, 8809–8823 (2005).

    Article  CAS  Google Scholar 

  30. Haas-Kogan, D. et al. Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr. Biol. 8, 1195–1198 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank A. Abbas, S. Abrams, M. Berger, D. Deen, H. Dooms, E. Holland, L. Lanier, J. Sampson and P. Srivastava for review, discussion and input at various stages of this manuscript. The authors also thank L. Chen (Johns Hopkins University), and G. Wang and J. Floros (Pennsylvania State University) for providing constructs and advice; and C. Sison and R. Collins for technical support. A.T.P. was supported in part by a K08 grant from the National Institute of Neurological Disorder and Stroke, a career development award from Brain Specialized Programs of Research Excellence (SPORE) of the National Cancer Institute, the Seibrandt Vaccine Fund and the Khatib Foundation.

Author information

Authors and Affiliations

Authors

Contributions

A.T.P. designed the experiments, performed the preliminary experiments and wrote the manuscript. J.S.W. and I.F.P. performed confirmatory functional analysis. A.P. performed protein expression and RNA expression experiments. C.A.C., J.J.B., K.E.C. and J.C.M. performed the T-cell experiments. T.T. performed the immunohistochemistry analysis. M.C.J. characterized and cloned the T cells for functional experiments. P.S.M. characterized and provided the U87 PTEN-positive cells. D.S. characterized the PTEN status of primary samples. R.O.P. characterized, cloned the transformed human astrocytes and made significant contributions to the manuscript.

Corresponding author

Correspondence to Andrew T Parsa.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

B7-H1 protein but not transcript levels elevated and cell surface localized after Ras and/or Akt activation. (PDF 443 kb)

Supplementary Fig. 2

Inhibition and differential levels of Akt in glioma and genetically-modified NHA hTERT/E6/E7/Ras+/Akt+ lines. (PDF 2631 kb)

Supplementary Fig. 3

Densitometric analysis of stably transfected constructs for wildtype and mutant S6K1 and eIF4E, respectively, into PTEN wildtype (E6/E7) and rescued (U87 PTEN+) cell lines (*P<0.05). (PDF 836 kb)

Supplementary Fig. 4

Stable transfection of B7-H1 into U87 PTEN+ and SF767 (*P<0.05). (PDF 143 kb)

Supplementary Table 1

Summary of genetic modifications and effects in normal human astrocytoma (NHA) cell lines. (PDF 37 kb)

Supplementary Table 2

Summary of all NHA genetically-modified cell lines. (PDF 36 kb)

Supplementary Table 3

Summary of clinical data for primary glioblastoma tumor samples. (PDF 38 kb)

Supplementary Methods (PDF 58 kb)

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Parsa, A., Waldron, J., Panner, A. et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13, 84–88 (2007). https://doi.org/10.1038/nm1517

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