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

Hum Pathol. 2016 Jun;52:9-18. doi: 10.1016/j.humpath.2016.01.010. Epub 2016 Feb 5.

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.

Keywords: Immunohistochemistry; Mesothelioma; PD-1; PD-L1; Pleura; TILs; TLR3.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • B7-H1 Antigen / analysis*
  • Biomarkers, Tumor / analysis*
  • CD3 Complex / analysis
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Female
  • Humans
  • Immunohistochemistry
  • Immunotherapy
  • Kaplan-Meier Estimate
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Male
  • Mesothelioma / immunology*
  • Mesothelioma / mortality
  • Mesothelioma / pathology
  • Mesothelioma / therapy
  • Mesothelioma, Malignant
  • Middle Aged
  • Patient Selection
  • Pleural Neoplasms / immunology*
  • Pleural Neoplasms / mortality
  • Pleural Neoplasms / pathology
  • Pleural Neoplasms / therapy
  • Predictive Value of Tests
  • Programmed Cell Death 1 Receptor / analysis*
  • Proportional Hazards Models
  • Time Factors
  • Toll-Like Receptor 3 / analysis*
  • Young Adult

Substances

  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • CD3 Complex
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • TLR3 protein, human
  • Toll-Like Receptor 3