Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study

Our plain-English summary of Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study, by L. Brcic, T. Klikovits, Z. Megyesfalvi, et al (Translational Lung Cancer Research, 2021).

The study

• Authors: L. Brcic, T. Klikovits, Z. Megyesfalvi, B. Mosleh, K. Sinn, R. Hritcu, V. Laszlo, T. Cufer, A. Rozman, I. Kern, K. Mohorcic, M. Jakopovic, M. Samarzija, S. Seiwerth, V. Kolek, O. Fischer, P. Jakubec, J. Škarda, B. Gieszer, B. Hegedus, J. Fillinger, F. Renyi-Vamos, A. Buder, A. Bilecz, W. Berger, M. Grusch, K. Hoetzenecker, W. Klepetko, M.A. Hoda, M. Filipits, B. Dome
• Journal: Translational Lung Cancer Research
• Published: 2021;10(4):1594-1607
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM).

Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome.

Results: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [≥1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 vs. 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS.

Conclusions: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.

2021 Translational Lung Cancer Research. All rights reserved.

In plain English

This retrospective study included 203 patients with malignant pleural mesothelioma. They were diagnosed in 2000 to 2016 at five Central European centers; none received immunotherapy. The authors stained stored tumor tissue for the immune-related proteins PD-L1 and PD-1. They analyzed PD-L1 in tumor cells and tumor-infiltrating lymphocytes (immune cells inside the tumor), but PD-1 only in lymphocytes, as no tumor cells showed it, and compared results with patient features and survival. The study did not examine asbestos exposure. High PD-L1 in tumor cells (over 10% of cells) was found in 18 of 203 patients. Their median overall survival was 6.3 months, versus 15.1 months for those at 10% or less. The link stayed statistically significant after adjusting for age, gender, tissue subtype, stage and treatment in 126 patients with complete data. PD-L1 and PD-1 in immune cells showed no significant link with survival. No protein level was significantly linked with stage or tissue subtype. The authors concluded that high tumor-cell PD-L1 is an independent marker of worse survival. They noted the study was retrospective with no validation set.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective multicenter cohort study of stored tumor tissue (immunohistochemistry) with survival analysis
• Who was studied: 203 patients with histologically confirmed malignant pleural mesothelioma diagnosed between 2000 and 2016 at 5 Central European centers (Zagreb, Budapest, Vienna, Golnik, Olomouc). 151 were epithelioid, 39 non-epithelioid and 13 not otherwise specified. Median age was 64 years and 71.4% were male. No patient received immunotherapy.
• Exposure: Asbestos exposure was not assessed. The factor studied was protein expression: PD-L1 in tumor cells and tumor-infiltrating lymphocytes, and PD-1 in tumor-infiltrating lymphocytes only. Each was classed as low (0 to 10% of cells positive) or high (more than 10% positive).
• Main results:
  • Tumor cells: 152 of 203 cases (75%) showed no PD-L1. 51 (25%) showed any PD-L1 (1% or more), of whom 18 were classed high (more than 10%).
  • Immune cells (tumor-infiltrating lymphocytes), 165 patients with suitable tissue: PD-L1 of 1% or more in 13 (8%). Only 1 case exceeded 10%.
  • PD-1 was measured in the immune cells of 164 patients. 83 (50%) were positive (1% or more) and 39 (24%) had more than 10%. No PD-1 was seen on tumor cells.
  • There was no significant association between PD-L1 or PD-1 levels and age, gender, histological subtype or tumor stage.
  • Median overall survival was 6.3 months for patients with high (more than 10%) tumor-cell PD-L1, versus 15.1 months for those with low PD-L1. The univariate hazard ratio for low versus high was 0.39 (95% CI 0.18 to 0.86), P less than 0.001.
  • In the multivariate analysis of 126 patients with complete data, tumor-cell PD-L1 at a 10% cut-off remained a significant factor for survival: low versus high, HR 0.405 (95% CI 0.216 to 0.759), P=0.005. An exploratory analysis of all 203 cases using imputed data gave HR 0.443, P=0.004.
  • Immune-cell PD-L1 was not significantly linked with survival: median 15.1 months (below 1%) versus 11.8 months (1% or more), HR 0.82, P=0.508. Immune-cell PD-1 also showed no survival difference across three levels (P=0.703).
  • In the multivariate model, three other factors were also independently associated with survival: epithelioid subtype (HR 0.504, P=0.009), stage I to II (HR 0.545, P=0.007), and multimodality treatment including surgery (HR 0.351, P less than 0.001).
• The authors' conclusion: The authors concluded that high (more than 10%) tumor-cell PD-L1 expression is associated with a clinically relevant survival disadvantage and is an independent prognostic factor in malignant pleural mesothelioma. They also concluded that PD-1 expression in immune cells may not serve as a suitable prognostic marker.
• Limitations the authors state:
  • The study was retrospective and had no validation set, so the authors said results should be interpreted with caution.
  • The results apply mainly to the E1L3N antibody used, because different antibody clones stain differently.
  • PD-L1 and PD-1 levels vary over time. Chemotherapy before tissue sampling, given in 23 cases, may have affected the results.

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Pleural Mesothelioma, PD-1/PD-L1, Immunotherapy, Tumor-Infiltrating Lymphocytes, Immunohistochemistry, Histological Subtype, Median Overall Survival.

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