Prognostic significance of PD-1/PD-L1 expression in uveal melanoma: correlation with tumor-infiltrating lymphocytes and
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ORIGINAL ARTICLE
Prognostic significance of PD‑1/PD‑L1 expression in uveal melanoma: correlation with tumor‑infiltrating lymphocytes and clinicopathological parameters Lata Singh1,2,4 · Mithalesh Kumar Singh1 · Maria Cristina Kenney2 · Martine J. Jager3 · Moshahid Alam Rizvi4 · Rachna Meel5 · Neiwete Lomi5 · Sameer Bakhshi6 · Seema Sen1 · Seema Kashyap1 Received: 8 May 2020 / Accepted: 19 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Uveal melanoma · Immunotherapy · Tumor-infiltrating lymphocytes · Interferon gamma Abbreviations AJCC American Joint Committee on Cancer IHC Immunohistochemistry IFN-γ Interferon gamma Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02773-8) contains supplementary material, which is available to authorized users.
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
* Seema Kashyap [email protected]
3
Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
Lata Singh [email protected]
4
Biosciences, Jamia Millia Islamia, New Delhi, India
5
Department of Ophthalmology, Dr. R. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
6
Department of Medical Onc
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