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

Nature Medicine volume 13, pages 84–88 (2007)Cite this article

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.

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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.

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Authors and Affiliations

  1. Department of Neurological Surgery, University of California San Francisco, 505 Parnassus Avenue, M-779, San Francisco, 94143, California, USA

    Andrew T Parsa, James S Waldron, Amith Panner, Courtney A Crane, Ian F Parney, Jeffrey J Barry, Kristine E Cachola, Joseph C Murray, Tarik Tihan, David Stokoe & Russell O Pieper

  2. Division of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, 91010, California, USA

    Michael C Jensen

  3. Department of Pathology and Laboratory Medicine, the Henry E. Singleton Brain Cancer Research Program at the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, California, USA

    Paul S Mischel

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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.

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Correspondence to Andrew T Parsa.

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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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