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Prognostic significance of PD-1/PD-L1 expression in uveal melanoma: correlation with tumor-infiltrating lymphocytes and clinicopathological parameters

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Abstract

Background

To understand how to improve the effect of immune checkpoint inhibitors in uveal melanoma (UM), we need a better understanding of the expression of PD-1 and PD-L1, their relation with the presence of tumor-infiltrating lymphocytes (TILs), and their prognostic relevance in UM patients.

Materials and methods

Expression of PD-1 and PD-L1 was assessed in 71 UM tissue samples by immunohistochemistry and quantitative real-time PCR (qRT-PCR), and further validated by western blotting. The effect of interferon gamma (IFN-γ) on PD-1/PD-L1 expression was determined on four UM cell lines.

Results

Immunoreactivity of PD-1 was found in 30/71 cases and of PD-L1 in 44/71 UM samples. Tumor-infiltrating lymphocytes were found in 46% of UM tissues. PD-1 was expressed on TILs while tumor cells expressed PD-L1. UM with and without TILs showed expression of PD-1 in 69% and 18% cases, respectively (p = 0.001). Similarly, PD-L1 was found in 75% of UM with TILs and in 50% of cases without TILs, respectively (p = 0.03). DFS rate were lower in patients with TILs with expression of PD-1 and PD-L1, but the rate of DFS was higher with expression of PD-L1 in patients without TILs. After treatment of UM cell lines with IFN-γ, PD-1 expression was induced in all UM cell lines whereas PD-L1 expression was found at a lower level in untreated cells, while expression also increased following treatment with IFN-γ.

Conclusion

Our study suggests that increased infiltration with TILs promotes the aggressive behavior and suppresses the immune response of UM cells, thereby inhibiting immunotherapy.

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Abbreviations

AJCC:

American Joint Committee on Cancer

IHC:

Immunohistochemistry

IFN-γ:

Interferon gamma

MVD:

Microvascular density

PD-1:

Programmed death-1

PD-L1:

Programmed death-ligand 1

qRT-PCR:

Quantitative real-time polymerase chain reaction

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

TILs:

Tumor-infiltrating lymphocytes

UM:

Uveal melanoma

References

  1. Singh AD, Bergman L, Seregard S (2005) Uveal melanoma: epidemiologic aspects. Ophthalmol Clin North Am 18(1):75–84. https://doi.org/10.1016/j.ohc.2004.07.002

    Article  PubMed  Google Scholar 

  2. Kashyap S, Meel R, Singh L, Singh M (2016) Uveal melanoma. Semin Diagn Pathol 33(3):141–147. https://doi.org/10.1053/j.semdp.2015.10.005

    Article  PubMed  Google Scholar 

  3. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM (2010) Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330(6009):1410–1413. https://doi.org/10.1126/science.1194472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Seibel I, Cordini D, Rehak M, Hager A, Riechardt AI, Boker A, Heufelder J, Weber A, Gollrad J, Besserer A, Joussen AM (2015) Local recurrence after primary proton beam therapy in uveal melanoma: risk factors, retreatment approaches, and outcome. Am J Ophthalmol 160(4):628–636. https://doi.org/10.1016/j.ajo.2015.06.017

    Article  PubMed  Google Scholar 

  5. Weis E, Salopek TG, McKinnon JG, Larocque MP, Temple-Oberle C, Cheng T, McWhae J, Sloboda R, Shea-Budgell M (2016) Management of uveal melanoma: a consensus-based provincial clinical practice guideline. Curr Oncol 23(1):e57-64. https://doi.org/10.3747/co.23.2859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nathan P, Cohen V, Coupland S, Curtis K, Damato B, Evans J, Fenwick S, Kirkpatrick L, Li O, Marshall E, McGuirk K, Ottensmeier C, Pearce N, Salvi S, Stedman B, Szlosarek P, Turnbull N (2015) Uveal melanoma UK national guidelines. Eur J Cancer 51(16):2404–2412. https://doi.org/10.1016/j.ejca.2015.07.013

    Article  CAS  PubMed  Google Scholar 

  7. Rospond-Kubiak I, Damato B (2014) The surgical approach to the management of anterior uveal melanomas. Eye (Lond) 28(6):741–747. https://doi.org/10.1038/eye.2014.74

    Article  CAS  Google Scholar 

  8. Pereira PR, Odashiro AN, Lim LA, Miyamoto C, Blanco PL, Odashiro M, Maloney S, De Souza DF, Burnier MN Jr (2013) Current and emerging treatment options for uveal melanoma. Clin Ophthalmol 7:1669–1682. https://doi.org/10.2147/opth.S28863

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sato T (2010) Locoregional management of hepatic metastasis from primary uveal melanoma. Semin Oncol 37(2):127–138. https://doi.org/10.1053/j.seminoncol.2010.03.014

    Article  PubMed  Google Scholar 

  10. Komatsubara KM, Carvajal RD (2017) Immunotherapy for the treatment of Uveal melanoma: current status and emerging therapies. Curr Oncol Rep 19(7):45. https://doi.org/10.1007/s11912-017-0606-5

    Article  CAS  PubMed  Google Scholar 

  11. Zhou R, Caspi RR (2010) Ocular immune privilege. Biol Rep 1:2. https://doi.org/10.3410/b2-3

    Article  Google Scholar 

  12. Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18(6):884–901. https://doi.org/10.1016/j.devcel.2010.05.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Khong HT, Wang QJ, Rosenberg SA (2004) Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression. J Immunother 27(3):184–190. https://doi.org/10.1097/00002371-200405000-00002

    Article  PubMed  PubMed Central  Google Scholar 

  14. Denkert C, Loibl S, Noske A, Roller M, Muller B, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28(1):105–113

    Article  CAS  Google Scholar 

  15. Dieci M, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, Ficarra G, Mathieu M, Delaloge S, Curigliano G (2014) Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann Oncol 25(3):611–618

    Article  CAS  Google Scholar 

  16. Tougeron D, Fauquembergue E, Rouquette A, Le Pessot F, Sesboue R, Laurent M, Berthet P, Mauillon J, Di Fiore F, Sabourin JC, Michel P, Tosi M, Frebourg T, Latouche JB (2009) Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations. Mod Pathol 22(9):1186–1195. https://doi.org/10.1038/modpathol.2009.80

    Article  CAS  PubMed  Google Scholar 

  17. Lee JS, Won HS, Sun S, Hong JH, Ko YH (2018) Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a systematic review and meta-analysis. Medicine (Baltimore) 97(32):e11769. https://doi.org/10.1097/md.0000000000011769

    Article  CAS  Google Scholar 

  18. Ben-Avi R, Farhi R, Ben-Nun A, Gorodner M, Greenberg E, Markel G, Schachter J, Itzhaki O, Besser MJ (2018) Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients. Cancer Immunol Immunother 67(8):1221–1230. https://doi.org/10.1007/s00262-018-2174-4

    Article  CAS  PubMed  Google Scholar 

  19. Hwang W-T, Adams SF, Tahirovic E, Hagemann IS, Coukos G (2012) Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol 124(2):192–198

    Article  Google Scholar 

  20. Krishna Y, McCarthy C, Kalirai H, Coupland SE (2017) Inflammatory cell infiltrates in advanced metastatic uveal melanoma. Hum Pathol 66:159–166. https://doi.org/10.1016/j.humpath.2017.06.005

    Article  CAS  PubMed  Google Scholar 

  21. Sharma P, Allison JP (2015) The future of immune checkpoint therapy. Science 348(6230):56–61. https://doi.org/10.1126/science.aaa8172

    Article  CAS  PubMed  Google Scholar 

  22. Rossi E, Schinzari G, Zizzari IG, Maiorano BA, Pagliara MM, Sammarco MG, Fiorentino V, Petrone G, Cassano A, Rindi G, Bria E, Blasi MA, Nuti M, Tortora G (2019) Immunological backbone of uveal melanoma: is there a rationale for immunotherapy? Cancers (Basel) 11:8. https://doi.org/10.3390/cancers11081055

    Article  CAS  Google Scholar 

  23. Pötzl J, Roser D, Bankel L, Hömberg N, Geishauser A, Brenner CD, Weigand M, Röcken M, Mocikat R (2017) Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN-γ and induces NK cell-dependent lymphoma control without other immunotherapies. Int J Cancer 140(9):2125–2133

    Article  Google Scholar 

  24. Hallermalm K, Seki K, De Geer A, Motyka B, Bleackley RC, Jager MJ, Froelich CJ, Kiessling R, Levitsky V, Levitskaya J (2008) Modulation of the tumor cell phenotype by IFN-gamma results in resistance of uveal melanoma cells to granule-mediated lysis by cytotoxic lymphocytes. J Immunol 180(6):3766–3774. https://doi.org/10.4049/jimmunol.180.6.3766

    Article  CAS  PubMed  Google Scholar 

  25. Ni L, Lu J (2018) Interferon gamma in cancer immunotherapy. Cancer Med 7(9):4509–4516. https://doi.org/10.1002/cam4.1700

    Article  PubMed  PubMed Central  Google Scholar 

  26. Manguso RT, Pope HW, Zimmer MD, Brown FD, Yates KB, Miller BC, Collins NB, Bi K, LaFleur MW, Juneja VR (2017) In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 547(7664):413–418

    Article  CAS  Google Scholar 

  27. Wierenga APA, Cao J, Luyten GPM, Jager MJ (2019) Immune checkpoint inhibitors in uveal and conjunctival melanoma. Int Ophthalmol Clin 59(2):53–63. https://doi.org/10.1097/iio.0000000000000263

    Article  PubMed  Google Scholar 

  28. Daniels AB, Veverka KK, Patel SN, Sculley L, Munn G, Pulido JS (2019) Computing uveal melanoma basal diameters: a comparative analysis of several novel techniques with improved accuracy. Int J Retina Vitreous 5:2. https://doi.org/10.1186/s40942-018-0151-x

    Article  PubMed  PubMed Central  Google Scholar 

  29. Shields CL, Furuta M, Thangappan A, Nagori S, Mashayekhi A, Lally DR, Kelly CC, Rudich DS, Nagori AV, Wakade OA, Mehta S, Forte L, Long A, Dellacava EF, Kaplan B, Shields JA (2009) Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol 127(8):989–998. https://doi.org/10.1001/archophthalmol.2009.208

    Article  PubMed  Google Scholar 

  30. Makitie T, Summanen P, Tarkkanen A, Kivela T (2001) Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci 42(7):1414–1421

    CAS  PubMed  Google Scholar 

  31. Makitie T, Summanen P, Tarkkanen A, Kivela T (1999) Microvascular density in predicting survival of patients with choroidal and ciliary body melanoma. Invest Ophthalmol Vis Sci 40(11):2471–2480

    CAS  PubMed  Google Scholar 

  32. Jager MJ, Magner JA, Ksander BR, Dubovy SR (2016) Uveal melanoma cell lines: where do they come from? (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc 114:T5

    PubMed  PubMed Central  Google Scholar 

  33. De Waard-Siebinga I, Blom DJ, Griffioen M, Schrier PI, Hoogendoorn E, Beverstock G, Danen EH, Jager MJ (1995) Establishment and characterization of an uveal-melanoma cell line. Int J Cancer 62(2):155–161. https://doi.org/10.1002/ijc.2910620208

    Article  PubMed  Google Scholar 

  34. Chen PW, Murray TG, Uno T, Salgaller ML, Reddy R, Ksander BR (1997) Expression of MAGE genes in ocular melanoma during progression from primary to metastatic disease. Clin Exp Metastasis 15(5):509–518. https://doi.org/10.1023/a:1018479011340

    Article  CAS  PubMed  Google Scholar 

  35. Li Y, Liang L, Dai W, Cai G, Xu Y, Li X, Li Q, Cai S (2016) Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer. Mol Cancer 15(1):55. https://doi.org/10.1186/s12943-016-0539-x

    Article  PubMed  PubMed Central  Google Scholar 

  36. Oliva M, Rullan AJ, Piulats JM (2016) Uveal melanoma as a target for immune-therapy. Ann Transl Med 4(9):172. https://doi.org/10.21037/atm.2016.05.04

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zoroquiain P, Esposito E, Logan P, Aldrees S, Dias AB, Mansure JJ, Santapau D, Garcia C, Saornil MA, Belfort Neto R, Burnier MN (2018) Programmed cell death ligand-1 expression in tumor and immune cells is associated with better patient outcome and decreased tumor-infiltrating lymphocytes in uveal melanoma. Mod Pathol 31(8):1201–1210. https://doi.org/10.1038/s41379-018-0043-5

    Article  CAS  PubMed  Google Scholar 

  38. de la Cruz PO (1990) Lymphocytic infiltration in uveal malignant melanoma. Cancer 65(1):112–115. https://doi.org/10.1002/1097-0142(19900101)65:1%3c112::aid-cncr2820650123%3e3.0.co;2-x

    Article  PubMed  Google Scholar 

  39. Whelchel JC, Farah SE, McLean IW, Burnier MN (1993) Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. Invest Ophthalmol Vis Sci 34(8):2603–2606

    CAS  PubMed  Google Scholar 

  40. Bronkhorst IH, Vu TH, Jordanova ES, Luyten GP, Burg SH, Jager MJ (2012) Different subsets of tumor-infiltrating lymphocytes correlate with macrophage influx and monosomy 3 in uveal melanoma. Invest Ophthalmol Vis Sci 53(9):5370–5378. https://doi.org/10.1167/iovs.11-9280

    Article  CAS  PubMed  Google Scholar 

  41. Bronkhorst IH, Jager MJ (2013) Inflammation in uveal melanoma. Eye (Lond) 27(2):217–223. https://doi.org/10.1038/eye.2012.253

    Article  CAS  Google Scholar 

  42. Gezgin G, Dogrusoz M, van Essen TH, Kroes WGM, Luyten GPM, van der Velden PA, Walter V, Verdijk RM, van Hall T, van der Burg SH, Jager MJ (2017) Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment. Cancer Immunol Immunother 66(7):903–912. https://doi.org/10.1007/s00262-017-1991-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Xue M, Shang J, Chen B, Yang Z, Song Q, Sun X, Chen J, Yang J (2019) Identification of prognostic signatures for predicting the overall survival of uveal melanoma patients. J Cancer 10(20):4921–4931. https://doi.org/10.7150/jca.30618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kaliki S, Shields CL, Shields JA (2015) Uveal melanoma: estimating prognosis. Indian J Ophthalmol 63(2):93–102. https://doi.org/10.4103/0301-4738.154367

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264

    Article  CAS  Google Scholar 

  46. Dearman R, Moussavi A, Kemeny D, Kimber I (1996) Contribution of CD4+ and CD8+ T lymphocyte subsets to the cytokine secretion patterns induced in mice during sensitization to contact and respiratory chemical allergens. Immunology 89(4):502–510

    Article  CAS  Google Scholar 

  47. Yang W, Chen PW, Li H, Alizadeh H, Niederkorn JY (2008) PD-L1: PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro. Invest Ophthalmol Vis Sci 49(6):2518–2525. https://doi.org/10.1167/iovs.07-1606

    Article  PubMed  PubMed Central  Google Scholar 

  48. Niederkorn JY (2009) Immune escape mechanisms of intraocular tumors. Prog Retin Eye Res 28(5):329–347. https://doi.org/10.1016/j.preteyeres.2009.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The work was supported by Department for Science and Technology (DST), Govt. of India for providing National Post-Doctoral fellowship (N-PDF) to Dr. Lata Singh and conducting this research (NPDF/2016/000903).

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The authors have no proprietary or commercial interest in any materials discussed in this article.

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Authors and Affiliations

  1. Department of Ocular Pathology, Dr. R P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India

    Lata Singh, Mithalesh Kumar Singh, Seema Sen & Seema Kashyap

  2. Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, USA

    Lata Singh & Maria Cristina Kenney

  3. Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands

    Martine J. Jager

  4. Biosciences, Jamia Millia Islamia, New Delhi, India

    Lata Singh & Moshahid Alam Rizvi

  5. Department of Ophthalmology, Dr. R. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India

    Rachna Meel & Neiwete Lomi

  6. Department of Medical Oncology, All India Institute of Medical Sciences, IRCH, New Delhi, India

    Sameer Bakhshi

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  1. Lata Singh
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Contributions

Conception and study design: LS and MKS; clinicopathological data analysis: LS, MKS and SK; in vitro data analysis: LS and MCK; enucleated sample: RM and NL; follow-up of the patients: NL and SB; pathology slide review: SK and SS; cell lines provider: MJJ; manuscript editing: MCK, MJJ, LS, MKS and SK; all the authors finally approved the manuscript version to be published.

Corresponding author

Correspondence to Seema Kashyap.

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Conflict of interest

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Ethics approval

Human subjects were included in this study. Informed consent was obtained from all patients before participation in this study. All procedures were approved by the institutional ethics committee, All India Institute of Medical Sciences (AIIMS), New Delhi, India (Ref. No. IEC-424/RP-6/2016) and were conducted in accordance with the tenets of the Declaration of Helsinki for experiments involving humans.

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Consent for publication was obtained from all patients for collection of tissue samples prior to the surgery.

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Singh, L., Singh, M.K., Kenney, M.C. et al. Prognostic significance of PD-1/PD-L1 expression in uveal melanoma: correlation with tumor-infiltrating lymphocytes and clinicopathological parameters. Cancer Immunol Immunother 70, 1291–1303 (2021). https://doi.org/10.1007/s00262-020-02773-8

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