title: Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas.
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.
authors.affiliation: Département d'Anatomie et de Cytologie Pathologiques, Pôle de Biologie et de Pathologie, CHU A Michallon, CS 10217, 38043 Grenoble, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Combaz-Lair
authors.affiliation: Département de Biopathologie MESOPATH, Centre Léon Bérard, 69008 Lyon, U1086 INSERM-UCBN "Cancers & Préventions", Caen, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Galateau-Sallé
authors.affiliation: Plateforme Hospitalière de Génétique Moléculaire des Cancers, Pôle de Biologie et de Pathologie, CHU A Michallon, CS 10217, 38043 Grenoble, Université Joseph Fourier INSERM U 823, Institut A. Bonniot, 38700 La Tronche, France.
authors.forename: Anne
authors.initials: A
authors.lastname: McLeer-Florin
authors.affiliation: Département de Biopathologie - Registre MESONAT, Centre Léon Bérard, 69008 Lyon, U1086 INSERM-UCBN "Cancers & Préventions", Caen, France.
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Le Stang
authors.affiliation: Département d'Anatomie et de Cytologie Pathologiques, Pôle de Biologie et de Pathologie, CHU A Michallon, CS 10217, 38043 Grenoble, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: David-Boudet
authors.affiliation: Unité d'Oncologie Thoracique, Clinique de Pneumologie, Pôle Thorax et Vaisseaux, CHU A Michallon, CS 10217, 38043 Grenoble, Université Joseph Fourier - INSERM U 823, Institut A. Bonniot, 38700 La Tronche, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Duruisseaux
authors.affiliation: Clinique Universitaire de Radiologie et Imagerie Médicale, CHU A Michallon, CS 10217, 38043 Grenoble, Université Joseph Fourier INSERM U 823, Institut A. Bonniot, 38700 La Tronche, France.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Ferretti
authors.affiliation: Département d'Anatomie et de Cytologie Pathologiques, Pôle de Biologie et de Pathologie, CHU A Michallon, CS 10217, 38043 Grenoble, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM Unité Mixte de Recherche 1052/Centre National de la Recherche Scientifique 5286, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Lebecque
authors.affiliation: Département de Biopathologie, Centre Léon Bérard, 69008 Lyon, Université Joseph Fourier INSERM U 823, Institut A. Bonniot, 38700 La Tronche, France. Electronic address: sylvie.lantuejoul@lyon.unicancer.fr.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lantuejoul
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D017252:CD3 Complex / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D018579:Patient Selection; D010997:Pleural Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011237:Predictive Value of Tests; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis*; D016016:Proportional Hazards Models; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000032:analysis*; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D017252:CD3 Complex; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3
keywords: Immunohistochemistry; Mesothelioma; PD-1; PD-L1; Pleura; TILs; TLR3