. 2016 May; 76(9):925-45.
doi: 10.1007/s40265-016-0588-x.

Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 Expression a Biomarker for Patient Selection?

Lucia Festino 1 Gerardo Botti 1 Paul Lorigan 2 Giuseppe V Masucci 3 Jason D Hipp 4 Christine E Horak 4 Ignacio Melero 5 Paolo A Ascierto 6 
  • PMID: 27229745
  •     63 References
  •     51 citations


Strategies to help improve the efficacy of the immune system against cancer represent an important innovation, with recent attention having focused on anti-programmed death (PD)-1/PD-ligand 1 (L1) monoclonal antibodies. Clinical trials have shown objective clinical activity of these agents (e.g., nivolumab, pembrolizumab) in several malignancies, including melanoma, non-small-cell lung cancer, bladder cancer, squamous head and neck cancer, renal cell cancer, ovarian cancer, microsatellite-unstable colorectal cancer, and Hodgkin's lymphoma. Expression of PD-L1 in the tumor microenvironment appears to be crucial for therapeutic activity, and initial trials suggested positive PD-L1 tumor expression was associated with higher response rates. However, subsequent observations have questioned the prospect of using PD-L1 expression as a biomarker for selecting patients for therapy, especially since many patients considered PD-L1-negative experience a benefit from treatment. Importantly, there is not yet a definitive test for determination of PD-L1 and a cut-off reference for PD-L1-positive status has not been established. Immunohistochemistry with different antibodies and different thresholds has been used to define PD-L1 positivity (1-50 %), with no clear superiority of one threshold over another for identifying which patients respond. Moreover, the type of cells on which PD-L1 expression is most relevant is not yet clear, with immune infiltrate cells and tumor cells both being used. In conclusion, while PD-L1 expression is often a predictive factor for treatment response, it must be complemented by other biomarkers or histopathologic features, such as the composition and amount of inflammatory cells in the tumor microenvironment and their functional status. Multi-parameter quantitative or semi-quantitative algorithms may become useful and reliable tools to guide patient selection.

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Uncovering PD-L1 and CD8+ TILS Expression and Clinical Implication in Cervical Squamous Cell Carcinoma.
Jingjing Chen, Ping Gu, Haibo Wu.
Biomed Res Int, 2020 Sep 05; 2020. PMID: 32884946    Free PMC article.
MHC Class 1 and PDL-1 Status of Primary Tumor and Lymph Node Metastatic Tumor Tissue in Gastric Cancers.
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Gastroenterol Res Pract, 2019 Mar 19; 2019. PMID: 30881447    Free PMC article.
Immune Checkpoint Ligand Reverse Signaling: Looking Back to Go Forward in Cancer Therapy.
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Cancers (Basel), 2019 May 08; 11(5). PMID: 31060225    Free PMC article.
Prognostic and clinicopathological roles of programmed death-ligand 1 (PD-L1) expression in thymic epithelial tumors: A meta-analysis.
Hyun Min Koh, Bo Gun Jang, Hyun Ju Lee, Chang Lim Hyun.
Thorac Cancer, 2020 Sep 15; 11(11). PMID: 32926538    Free PMC article.
Exosomal PD-L1: New Insights Into Tumor Immune Escape Mechanisms and Therapeutic Strategies.
Kaijian Zhou, Shu Guo, +2 authors, Guoxin Liang.
Front Cell Dev Biol, 2020 Nov 13; 8. PMID: 33178688    Free PMC article.
Immuno-PET Imaging of the Programmed Cell Death-1 Ligand (PD-L1) Using a Zirconium-89 Labeled Therapeutic Antibody, Avelumab.
Elaine M Jagoda, Olga Vasalatiy, +15 authors, Peter L Choyke.
Mol Imaging, 2019 May 03; 18. PMID: 31044647    Free PMC article.
The clinical significance of HERV-H LTR -associating 2 expression in cervical adenocarcinoma.
Jung Mi Byun, Hwa Jin Cho, +10 authors, Dae Hoon Jeong.
Medicine (Baltimore), 2021 Jan 13; 100(1). PMID: 33429737    Free PMC article.
Establishing peripheral PD-L1 as a prognostic marker in hepatocellular carcinoma patients: how long will it come true?
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Cancer Gene Ther, 2019 Jun 22; 27(3-4). PMID: 31222183
Response to Neoadjuvant Chemotherapy in Locally Advanced Cervical Cancer: The Role of Immune-related Factors.
Innocenza Palaia, Federica Tomao, +9 authors, Pierluigi Benedetti Panici.
In Vivo, 2021 Feb 25; 35(2). PMID: 33622931    Free PMC article.
CD8 lymphocytes in tumors and nonsynonymous mutational load correlate with prognosis of bladder cancer patients treated with immune checkpoint inhibitors.
Boya Deng, Jae-Hyun Park, +6 authors, Yusuke Nakamura.
Cancer Rep (Hoboken), 2018 Jun 01; 1(1). PMID: 32729250    Free PMC article.
Rectosigmoid-Junction Squamous Cell Carcinoma With pMMR/MSS Achieved a Partial Response Following PD-1 Blockade Combined With Chemotherapy: A Case Report.
Yanxin He, Lunqing Wang, +6 authors, Haiping Song.
Front Oncol, 2021 Jun 12; 11. PMID: 34113555    Free PMC article.
Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer.
Liying Sha, Zhiqiang Lv, +4 authors, Hui Zhang.
Mol Med Rep, 2021 Jun 11; 24(2). PMID: 34109434    Free PMC article.
Precision Medicine in Oncology: A Review of Multi-Tumor Actionable Molecular Targets with an Emphasis on Non-Small Cell Lung Cancer.
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J Pers Med, 2021 Jul 03; 11(6). PMID: 34198738    Free PMC article.
Clinical and Prognostic Value of Antigen-Presenting Cells with PD-L1/PD-L2 Expression in Ovarian Cancer Patients.
Anna Pawłowska, Agnieszka Kwiatkowska, +5 authors, Iwona Wertel.
Int J Mol Sci, 2021 Nov 14; 22(21). PMID: 34768993    Free PMC article.
Programmed death ligand 2 expression plays a limited role in adenocarcinomas of the gastroesophageal junction after preoperative chemotherapy.
Gerd Jomrich, Dagmar Kollmann, +10 authors, Sebastian F Schoppmann.
Eur Surg, 2021 Dec 07; 53(6). PMID: 34868284    Free PMC article.
In vitro characterization of a small molecule PD-1 inhibitor that targets the PD-l/PD-L1 interaction.
Chih-Hao Lu, Wei-Min Chung, +3 authors, Huey-En Tzeng.
Sci Rep, 2022 Jan 09; 12(1). PMID: 34996924    Free PMC article.