title: The PD-L1/PD-1 pathway promotes dysfunction, but not "exhaustion", in tumor-responding T cells from pleural effusions in lung cancer patients.
abstract: Malignant pleural effusions are frequent in patients with advanced stages of lung cancer and are commonly infiltrated by lymphocytes and tumor cells. CD8+ T cells from these effusions have reduced effector functions. The programmed death receptor 1(PD-1)/programmed death ligand 1 (PD-L1) pathway is involved in T-cell exhaustion, and it might be responsible for T-cell dysfunction in lung cancer patients. Here, we show that PD-L1 is expressed on tumor cell samples from malignant effusions, on lung cancer cell lines, and, interestingly, on MRC-5 lung fibroblasts. PD-L1 was up-regulated in lung cancer cell lines upon treatment with IFN-gamma, but not under hypoxic conditions, as detected by RT-qPCR and flow cytometry. Blockade of PD-L1 on tumor cells restored granzyme-B expression in allogenic CD8+ T cells in vitro. Remarkably, pleural effusion CD8+ T cells that responded to the tumor antigens MAGE-3A and WT-1 (identified as CD137+ cells) were lower in frequency than CMV pp65-responding CD8+ T cells and did not have an exhausted phenotype (PD-1+ TIM-3+). Nonetheless, tumor-responding CD8+ T cells had a memory phenotype and expressed higher levels of PD-1. A PD-L1 blocking antibody increased the expression of granzyme-B and perforin on polyclonal- and tumor-stimulated CD8+ T cells. Taken together, our data show that rather than being exhausted, tumor-responding CD8+ T cells are not completely differentiated into effector cells and are prone to negative regulation by PD-L1. Hence, our study provides evidence that lung cancer patients respond to immunotherapy due to blockade of the PD-L1/PD-1 pathway.
authors.affiliation: Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias, "Ismael Cosio Villegas", Calzada de Tlalpan 4502, Col. Seccion XVI, 14080, Mexico City, Mexico. hpradog@yahoo.com.
authors.forename: Heriberto
authors.identifier: http://orcid.org/0000-0002-4932-3244
authors.initials: H
authors.lastname: Prado-Garcia
authors.affiliation: Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias, "Ismael Cosio Villegas", Calzada de Tlalpan 4502, Col. Seccion XVI, 14080, Mexico City, Mexico.
authors.forename: Susana
authors.initials: S
authors.lastname: Romero-Garcia
authors.affiliation: Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias, "Ismael Cosio Villegas", Calzada de Tlalpan 4502, Col. Seccion XVI, 14080, Mexico City, Mexico.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Puerto-Aquino
authors.affiliation: Clinica de Neumo-Oncologia, Instituto Nacional de Enfermedades Respiratorias, "Ismael Cosio Villegas", Calzada de Tlalpan 4502, Col. Seccion XVI, 14080, Mexico City, Mexico.
authors.forename: Uriel
authors.initials: U
authors.lastname: Rumbo-Nava
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D010996:Pleural Effusion / Q000276:immunology* / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: CD8+ T cell; Lung cancer; Melanoma-associated antigen 3 (MAGE-3A); PD-L1/PD-1 pathway; T-cell immunoglobulin domain and mucin domain protein 3 (TIM-3); Wilms tumor protein (WT-1)