Progression of Lung Cancer Is Associated with Increased Dysfunction of T Cells Defined by Coexpression of Multiple Inhibitory Receptors

BTLA公司 受体 生物 癌症 免疫系统 免疫疗法 免疫学 CD8型 肺癌 癌症研究 细胞毒性T细胞 T细胞 医学 内科学 体外 生物化学 遗传学
作者
Daniela S. Thommen,Jens Schreiner,Philipp Müller,Petra Herzig,Andreas Roller,Anton Belousov,Pablo Umaña,Pavel Pisa,Christian Klein,Marina Bacac,Ozana S. Fischer,Wolfgang Moersig,Spasenija Savic Prince,Victor Levitsky,Vaios Karanikas,Didier Lardinois,Alfred Zippelius
出处
期刊:Cancer immunology research [American Association for Cancer Research]
卷期号:3 (12): 1344-1355 被引量:329
标识
DOI:10.1158/2326-6066.cir-15-0097
摘要

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.
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