Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas

Our plain-English summary of Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas, by C. Combaz-Lair, F. Galateau-Sallé, A. McLeer-Florin, et al (Human Pathology, 2016).

The study

• Authors: C. Combaz-Lair, F. Galateau-Sallé, A. McLeer-Florin, N. Le Stang, L. David-Boudet, M. Duruisseaux, G.R. Ferretti, E. Brambilla, S. Lebecque, S. Lantuejoul
• Journal: Human Pathology
• Published: 2016;52:9-18
• Cited by: 72 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with no effective therapy. However PD-L1/PD-1 immunity checkpoint therapies gave encouraging results; TLR3 is a programmed death factor, which triggering up-regulates PD-L1. As PD-1/PD-L1 blocking antibodies could restore antitumor immune responses alone or in combination with TLR3 agonists, we investigated PD-L1/PD-1 and TLR3 expressions in MPM to select patients for immunotherapy. Sixty-eight pleural surgical specimens, including 58 MPM (epithelioid, n = 34; biphasic, n = 11; sarcomatoid, n = 13) and 10 benign lesions, were studied. PD-L1 expression was assessed using E1L3N and SP142 clones in tumor cells (TCs) and in tumor-infiltrating lymphocytes (TILs) (positivity threshold of 1%), and compared with overall survival. PD-1, CD3 and CD8 expression by TILs, and TLR3 expression by TCs were analyzed concomitantly. PD-L1 was more expressed by sarcomatoid subtype than by other MPM (62% versus 23% and 9% for E1L3N; 38% versus 11% for SP142) (P = .01 and .04, respectively). Specificity and sensitivity of E1L3N and SP142 were of 53% and 98%, and 90% and 86%, respectively. PD-L1 expression by TILs and TCs correlated for SP142 (P = .023), and PD-L1 SP142 expression by TCs was associated with shorter overall survival (P = .016). TLR3 was expressed in most MPM, but weakly in sarcomatoid MPM. We confirm by comparing two commercially available antibodies that PD-L1 expression is higher in sarcomatoid MPM and correlates with a shorter survival. Whereas TLR3 agonists could be tested in MPM expressing TLR3, the sarcomatoid subtype could benefit from anti-PD-L1/PD-1 therapies alone or in combination.

Copyright © 2016 Elsevier Inc. All rights reserved.

In plain English

This laboratory study examined 68 pleural surgical specimens stored at Grenoble University Hospital, France, from 1993 to 2014. There were 58 malignant pleural mesotheliomas (34 epithelioid, 11 biphasic, 13 sarcomatoid) and 10 benign lesions. All mesothelioma patients had stage III or IV disease. Asbestos exposure was not examined. The authors stained the tissue for immune markers, including PD-L1 (with two antibodies, E1L3N and SP142), PD-1 and TLR3. PD-L1 appeared on tumor cells in 29% of mesotheliomas with E1L3N and 17% with SP142. It was more frequent in sarcomatoid tumors (62% and 38%). Patients whose tumor cells showed PD-L1 with SP142 had shorter survival. Their two-year survival was 0%, against 19% (95% CI 8% to 31%) for patients without it. After accounting for age and tumor type, their risk of death was 2.2 times higher (95% CI 1.0 to 4.7). TLR3 was found in most mesotheliomas, less so in sarcomatoid tumors. The authors concluded that PD-L1 on tumor cells is a poor-prognostic factor. They suggested testing TLR3 agonists (drugs that activate TLR3) in most epithelioid and biphasic mesotheliomas, but not sarcomatoid ones.

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: Laboratory (immunohistochemistry) study of stored surgical tissue specimens, with survival analysis
• Who was studied: 68 pleural surgical specimens from Grenoble University Hospital, France, 1993 to 2014. There were 58 malignant pleural mesotheliomas (34 epithelioid, 13 sarcomatoid, 11 biphasic) from 45 men and 13 women, all at advanced stage III or IV, and 10 benign pleural lesions.
• Exposure: Asbestos exposure was not studied. The study measured immune markers in the tissue: PD-L1 (two antibody clones, E1L3N and SP142), PD-1, CD3, CD8 and TLR3.
• Main results:
  • PD-L1 was found on tumor cells in 29% of all malignant pleural mesotheliomas with the E1L3N antibody and in 17% with the SP142 antibody.
  • In sarcomatoid mesotheliomas, tumor-cell PD-L1 was found in 62% of cases with E1L3N and in 38% with SP142. Counting tumor cells and infiltrating lymphocytes together, PD-L1 was more frequent in sarcomatoid tumors than in other subtypes (p=0.01 and 0.04).
  • Using a 1% threshold, PD-L1 in tumor-infiltrating lymphocytes was correlated with PD-L1 in tumor cells only for the SP142 antibody.
  • Tumor-cell PD-L1 detected with SP142 was linked to shorter overall survival (p=0.016). PD-L1 detected with E1L3N was not.
  • Independently of tumor subtype and age, SP142 PD-L1 on tumor cells was linked to a 2.2 times higher risk of death at 2 years (HR 2.2, 95% CI 1.0 to 4.7). Two-year survival was 0% with PD-L1 and 19% (95% CI 8% to 31%) without it.
  • TLR3 was found in 96% of mesotheliomas and in all benign lesions. Mean TLR3 scores were lower in sarcomatoid tumors and benign lesions than in epithelioid and biphasic tumors (p=0.0001).
  • No statistical association was found between PD-L1 (either antibody) and PD-1 in tumor-infiltrating lymphocytes.
• The authors' conclusion: The authors concluded that TLR3 is expressed by most malignant pleural mesotheliomas, while PD-L1 is expressed in fewer than 20% and, on tumor cells, is a poor-prognostic factor. They suggested that TLR3 agonists could be tested in most epithelioid and biphasic tumors, with the exception of sarcomatoid ones. They added that, depending on PD-L1 status, anti-PD-L1 or anti-PD-1 therapies could be combined with them.
• Limitations the authors state:
  • The study included no lympho-histiocytoid mesothelioma cases.
  • The E1L3N antibody gave strong background staining, often non-specific staining inside the cells, compared with SP142.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Biomarker, PD-1/PD-L1, Pleural Mesothelioma, PD-L1, Immunotherapy, Epithelioid, Biphasic Mesothelioma, Sarcomatoid.

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