Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Basic Research

Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance

Prostate Cancer and Prostatic Diseases volume 18, pages 325–332 (2015)Cite this article

Subjects

Abstract

BACKGROUND:

Primary prostate cancers are infiltrated with programmed death-1 (PD-1) expressing CD8+ T-cells. However, in early clinical trials, men with metastatic castrate-resistant prostate cancer did not respond to PD-1 blockade as a monotherapy. One explanation for this unresponsiveness could be that prostate tumors generally do not express programmed death ligand-1 (PD-L1), the primary ligand for PD-1. However, lack of PD-L1 expression in prostate cancer would be surprising, given that phosphatase and tensin homolog (PTEN) loss is relatively common in prostate cancer and several studies have shown that PTEN loss correlates with PD-L1 upregulation—constituting a mechanism of innate immune resistance. This study tested whether prostate cancer cells were capable of expressing PD-L1, and whether the rare PD-L1 expression that occurs in human specimens correlates with PTEN loss.

METHODS:

Human prostate cancer cell lines were evaluated for PD-L1 expression and loss of PTEN by flow cytometry and western blotting, respectively. Immunohistochemical (IHC) staining for PTEN was correlated with PD-L1 IHC using a series of resected human prostate cancer samples.

RESULTS:

In vitro, many prostate cancer cell lines upregulated PD-L1 expression in response to inflammatory cytokines, consistent with adaptive immune resistance. In these cell lines, no association between PTEN loss and PD-L1 expression was apparent. In primary prostate tumors, PD-L1 expression was rare, and was not associated with PTEN loss.

CONCLUSIONS:

These studies show that some prostate cancer cell lines are capable of expressing PD-L1. However, in human prostate cancer, PTEN loss is not associated with PD-L1 expression, arguing against innate immune resistance as a mechanism that mitigates antitumor immune responses in this disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8: 793–800.

    Article  CAS  PubMed  Google Scholar 

  2. Zou W, Chen L . Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 2008; 8: 467–477.

    Article  CAS  PubMed  Google Scholar 

  3. Drake CG, Lipson EJ, Brahmer JR . Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat Rev Clin Oncol 2014; 11: 24–37.

    Article  CAS  PubMed  Google Scholar 

  4. Topalian SL, Drake CG, Pardoll DM . Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012; 24: 207–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pardoll DM . The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Topalian SL, Sznol M, Brahmer JR, McDermott DF, Smith DC, Gettinger SN et al. Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: survival and long-term safety in a phase I trial [abstract]. J Clin Oncol 2013; 31 (Suppl): 3002.

    Google Scholar 

  7. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28: 3167–3175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 2012; 4: 127ra37.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443–2454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Grosso JF, Horak CE, Inzunza D, Cardona DM, Simon JS, Gupta AK et al. Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538) [abstract]. J Clin Oncol 2013; 31 (Suppl): 3016.

    Google Scholar 

  11. 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 1999; 5: 1365–1369.

    Article  CAS  PubMed  Google Scholar 

  12. Pardoll D, Drake C . Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med 2012; 209: 201–209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 2007; 13: 84–88.

    Article  CAS  PubMed  Google Scholar 

  14. Crane C, Panner A, Murray J, Wilson S, Xu H, Chen L et al. PI (3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene 2009; 28: 306–312.

    Article  CAS  PubMed  Google Scholar 

  15. Sircar K, Yoshimoto M, Monzon FA, Koumakpayi IH, Katz RL, Khanna A et al. PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer. J Pathol 2009; 218: 505–513.

    Article  CAS  PubMed  Google Scholar 

  16. Lotan TL, Gurel B, Sutcliffe S, Esopi D, Liu W, Xu J et al. PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res 2011; 17: 6563–6573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yoshimoto M, Ding K, Sweet JM, Ludkovski O, Trottier G, Song KS et al. PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade. Mod Pathol 2013; 26: 435–447.

    Article  CAS  PubMed  Google Scholar 

  18. Antonarakis ES, Keizman D, Zhang Z, Gurel B, Lotan TL, Hicks JL et al. An immunohistochemical signature comprising PTEN, MYC, and Ki67 predicts progression in prostate cancer patients receiving adjuvant docetaxel after prostatectomy. Cancer 2012; 118: 6063–6071.

    Article  CAS  PubMed  Google Scholar 

  19. Pretlow TG, Wolman SR, Micale MA, Pelley RJ, Kursh ED, Resnick MI et al. Xenografts of primary human prostatic carcinoma. J Natl Cancer Inst 1993; 85: 394–398.

    Article  CAS  PubMed  Google Scholar 

  20. Koochekpour S, Maresh GA, Katner A, Parker‐Johnson K, Lee T, Hebert FE et al. Establishment and characterization of a primary androgen‐responsive African‐American prostate cancer cell line, E006AA. Prostate 2004; 60: 141–152.

    Article  PubMed  Google Scholar 

  21. Russell PJ, Kingsley EA . Human prostate cancer cell lines. In: Walker JM (ed), Prostate Cancer Methods and Protocols, Vol. 81. Springer: Berlin, Germany, 2003, pp 21–39.

  22. Korenchuk S, Lehr JE, MClean L, Lee YG, Whitney S, Vessella R et al. VCaP, a cell-based model system of human prostate cancer. In Vivo 2001; 15: 163–168.

    CAS  PubMed  Google Scholar 

  23. Haile ST, Bosch JJ, Agu NI, Zeender AM, Somasundaram P, Srivastava MK et al. Tumor cell programmed death ligand 1-mediated T-cell suppression is overcome by coexpression of CD80. J Immunol 2011; 186: 6822–6829.

    Article  CAS  PubMed  Google Scholar 

  24. Wang Y, Romigh T, He X, Tan M, Orloff M, Silverman R et al. Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers. Oncogene 2011; 30: 4327–4338.

    Article  CAS  PubMed  Google Scholar 

  25. Goldberg MV, Drake CG . LAG-3 in cancer immunotherapy. In: Dranoff G (ed), Cancer Immunology and Immunotherapy, Vol. 344. Springer: Berlin, Gemany, 2011, pp 269–278.

  26. Steimle V, Siegrist CA, Mottet A, Lisowska-Grospierre B, Mach B . Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science 1994; 265: 106–109.

    Article  CAS  PubMed  Google Scholar 

  27. Lin PY, Sun L, Thibodeaux SR, Ludwig SM, Vadlamudi RK, Hurez VJ et al. B7-H1-dependent sex-related differences in tumor immunity and immunotherapy responses. J Immunol 2010; 185: 2747–2753.

    Article  CAS  PubMed  Google Scholar 

  28. Jiang X, Chen S, Asara JM, Balk SP . Phosphoinositide 3-kinase pathway activation in phosphate and tensin homolog (PTEN)-deficient prostate cancer cells is independent of receptor tyrosine kinases and mediated by the p110beta and p110delta catalytic subunits. J Biol Chem 2010; 285: 14980–14989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. De Marzo AM, Marchi VL, Epstein JI, Nelson WG . Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol 1999; 155: 1985–1992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Herbst RS, Soria J, Kowanetz M, Fine GD, Hamid O, Gordon MS et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515: 563–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Degl'Innocenti E, Grioni M, Boni A, Camporeale A, Bertilaccio MT, Freschi M et al. Peripheral T-cell tolerance occurs early during spontaneous prostate cancer development and can be rescued by dendritic cell immunization. Eur J Immunol 2005; 35: 66–75.

    Article  CAS  PubMed  Google Scholar 

  32. Bai A, Higham E, Eisen HN, Wittrup KD, Chen J . Rapid tolerization of virus-activated tumor-specific CD8+ T-cells in prostate tumors of TRAMP mice. Proc Natl Acad Sci USA 2008; 105: 13003–13008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Atefi M, Avramis E, Lassen A, Wong DJ, Robert L, Foulad D et al. Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma. Clin Cancer Res 2014; 20: 3446–3457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mercader M, Bodner BK, Moser MT, Kwon PS, Park ES, Manecke RG et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc Natl Acad Sci USA 2001; 98: 14565–14570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gannon PO, Poisson AO, Delvoye N, Lapointe R, Mes-Masson A, Saad F . Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients. J Immunol Methods 2009; 348: 9–17.

    Article  CAS  PubMed  Google Scholar 

  36. Aragon-Ching JB, Williams KM, Gulley JL . Impact of androgen-deprivation therapy on the immune system: implications for combination therapy of prostate cancer. Front Biosci 2007; 12: 71.

    Article  Google Scholar 

  37. Drake CG . Prostate cancer as a model for tumour immunotherapy. Nat Rev Immunol 2010; 10: 580–593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank John T Isaacs, PhD, for donating the human prostate cancer cell lines for this study and Susan Dalrymple, BS, for instructing us on maintaining them. We also thank Olesya Chornoguz, PhD, for instruction regarding western blotting for phosphor-AKT. This work was funded by CGD: National Institutes of Health R01 CA127153, the Patrick C Walsh Fund, the One-in-Six Foundation, the Koch Foundation and the Prostate Cancer Foundation. AMD is the Virginia and Warren Schwerin Scholar and is supported by 1P50CA58236-15, the Patrick C Walsh Fund and the Prostate Cancer Foundation. AvB and MSL: NIH P30CA046934. This work was also supported by the NIH P30 CA006973 to the Johns Hopkins Sidney Kimmel Cancer Center.

Author information

Authors and Affiliations

  1. Department of Oncology, Johns Hopkins University, Baltimore, MD, USA

    A M Martin, T R Nirschl, C J Nirschl, B J Francica, C M Kochel, A van Bokhoven, A K Meeker, M S Lucia, R A Anders, A M DeMarzo & C G Drake

Authors
  1. A M Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T R Nirschl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C J Nirschl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B J Francica
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C M Kochel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A van Bokhoven
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A K Meeker
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M S Lucia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R A Anders
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A M DeMarzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C G Drake
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C G Drake.

Ethics declarations

Competing interests

CGD has consulted for Amplimmune, Bristol Myers Squibb (BMS), Merck and Roche-Genentech, all of whom have either anti-PD-1 or anti-PD-L1 reagents in various stages of clinical development. In addition, Drs Anders and Drake have received sponsored research funding from BMS. The first author Dr Martin has no conflict of interest to declare. All the other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Prostate Cancer and Prostatic Diseases website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martin, A., Nirschl, T., Nirschl, C. et al. Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance. Prostate Cancer Prostatic Dis 18, 325–332 (2015). https://doi.org/10.1038/pcan.2015.39

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/pcan.2015.39

This article is cited by

Search

Advanced search

Quick links