title: Progression of Lung Cancer Is Associated with Increased Dysfunction of T Cells Defined by Coexpression of Multiple Inhibitory Receptors.
abstract: Dysfunctional T cells present in malignant lesions are characterized by a sustained and highly diverse expression of inhibitory receptors, also referred to as immune checkpoints. Yet, their relative functional significance in different cancer types remains incompletely understood. In this study, we provide a comprehensive characterization of the diversity and expression patterns of inhibitory receptors on tumor-infiltrating T cells from patients with non-small cell lung cancer. In spite of the large heterogeneity observed in the amount of PD-1, Tim-3, CTLA-4, LAG-3, and BTLA expressed on intratumoral CD8(+) T cells from 32 patients, a clear correlation was established between increased expression of these inhibitory coreceptors and progression of the disease. Notably, the latter was accompanied by a progressively impaired capacity of T cells to respond to polyclonal activation. Coexpression of several inhibitory receptors was gradually acquired, with early PD-1 and late LAG-3/BTLA expression. PD-1 blockade was able to restore T-cell function only in a subset of patients. A high percentage of PD-1(hi) T cells was correlated with poor restoration of T-cell function upon PD-1 blockade. Of note, PD-1(hi) expression marked a particularly dysfunctional T-cell subset characterized by coexpression of multiple inhibitory receptors and thus may assist in identifying patients likely to respond to inhibitory receptor-specific antibodies. Overall, these data may provide a framework for future personalized T-cell-based therapies aiming at restoration of tumor-infiltrating lymphocyte effector functions.
authors.affiliation: Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. Laboratory of Cancer Immunology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland. alfred.zippelius@usb.ch daniela.thommen@usb.ch.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Thommen
authors.affiliation: Laboratory of Cancer Immunology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Schreiner
authors.affiliation: Laboratory of Cancer Immunology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Müller
authors.affiliation: Laboratory of Cancer Immunology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Herzig
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Roller
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
authors.forename: Anton
authors.initials: A
authors.lastname: Belousov
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Pablo
authors.initials: P
authors.lastname: Umana
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Pavel
authors.initials: P
authors.lastname: Pisa
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Marina
authors.initials: M
authors.lastname: Bacac
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Ozana S
authors.initials: OS
authors.lastname: Fischer
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Moersig
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Spasenija
authors.initials: S
authors.lastname: Savic Prince
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Victor
authors.initials: V
authors.lastname: Levitsky
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors.forename: Vaios
authors.initials: V
authors.lastname: Karanikas
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Lardinois
authors.affiliation: Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. Laboratory of Cancer Immunology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland. alfred.zippelius@usb.ch daniela.thommen@usb.ch.
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
mesh_terms: D000368:Aged; D019138:Antibodies, Blocking / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D018450:Disease Progression; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; C482586:BTLA protein, human; D060908:CTLA-4 Antigen; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human