RT Journal Article
SR Electronic
T1 Progression of Lung Cancer Is Associated with Increased Dysfunction of T Cells Defined by Coexpression of Multiple Inhibitory Receptors
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 1344
OP 1355
DO 10.1158/2326-6066.CIR-15-0097
VO 3
IS 12
A1 Thommen, Daniela S.
A1 Schreiner, Jens
A1 Müller, Philipp
A1 Herzig, Petra
A1 Roller, Andreas
A1 Belousov, Anton
A1 Umana, Pablo
A1 Pisa, Pavel
A1 Klein, Christian
A1 Bacac, Marina
A1 Fischer, Ozana S.
A1 Moersig, Wolfgang
A1 Savic Prince, Spasenija
A1 Levitsky, Victor
A1 Karanikas, Vaios
A1 Lardinois, Didier
A1 Zippelius, Alfred
YR 2015
UL http://cancerimmunolres.aacrjournals.org/content/3/12/1344.abstract
AB 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-1hi T cells was correlated with poor restoration of T-cell function upon PD-1 blockade. Of note, PD-1hi 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. Cancer Immunol Res; 3(12); 1344–55. ©2015 AACR.