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 a large heterogeneity observed in the expression levels of PD-1, Tim-3, CTLA-4, LAG-3 and BTLA on intratumoral CD8+ T cells from 32 patients, a clear correlation was established between increased expression of these inhibitory co-receptors and progression of the disease. Notably, the latter was accompanied by a progressively impaired capacity of T cells to respond to polyclonal activation. Co-expression 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 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 co-expression 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.
- Received April 10, 2015.
- Revision received June 9, 2015.
- Accepted July 1, 2015.
- Copyright © 2015, American Association for Cancer Research.