66P - Highly exhausted PD-1hi T cell subsets in human NSCLC are co-defined by the predominant expression of distinct inhibitory receptors and correlate w...

Date 15 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Poster lunch
Topics Cancer biology
Thoracic malignancies
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter Daniela Thommen
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors D. Thommen1, F. Uhlenbrock2, P. Herzig2, S. Savic Prince3, W. Moersig4, D. Lardinois4, A. Zippelius1
  • 1Medical Oncology, Universitätsspital Basel, 4031 - Basel/CH
  • 2Biomedicine, Laboratory of Cancer Immunology, 4031 - Basel/CH
  • 3Institute Of Pathology, Universitätsspital Basel, 4031 - Basel/CH
  • 4Thoracic Surgery, Universitätsspital Basel, 4031 - Basel/CH

Abstract

Background

Immune checkpoint blockade has shown encouraging results in non-small cell lung cancer. However, T cell dysfunction may present a significant obstacle to successful cancer immunotherapy. We have recently demonstrated that dysfunctional T cells present in malignant lesions are characterized by a sustained and highly diverse expression of inhibitory receptors (Thommen et al, Cancer Immunol Res, 2015; Schreiner et al, Oncoimmunology, 2015). Yet, their relative functional significance and impact on the response to immunotherapies in human cancer remains incompletely understood.

Methods

In this study, we provide a comprehensive characterization of the diversity, expression patterns, metabolic features and functional relevance of inhibitory receptors on tumor-infiltrating T cells with different states of exhaustion from patients with non-small cell lung cancer.

Results

In spite of a large heterogeneity observed in the expression levels of a diverse array of inhibitory receptors including PD-1, Tim-3, CTLA-4, LAG-3, BTLA, 2B4, CD160, TIGIT and KLRG-1 on intratumoral CD8+ T cells from NSCLC patients, a clear correlation was established between increased expression of these inhibitory co-receptors and progression of the disease. We identified PD-1hi expressing T cells as a surrogate for a highly dysfunctional T cell subset co-expressing multiple inhibitory receptors in contrast to their PD-1int and PD-1neg counterparts. The function of PD-1hi TILs could not be restored by PD-1 blockade in contrast to less dysfunctional subsets and high numbers of intratumoral PD-1hi T cells correlated with a decreased progression-free survival.

Conclusions

We show that T cells in NSCLC display various stages of dysfunction from which only a subset with moderate dysfunction can be rescued by PD-1 blockade, whereas highly exhausted PD-1hi T cells do not respond to PD-1 blockade alone and may be a marker of shorter survival. These data provide a framework for future personalized T cell-based therapies aiming at restoration of tumor-infiltrating lymphocyte effector functions.

Clinical trial identification

not applicable

Legal entity responsible for the study

University of Basel

Funding

Swiss National Science Foundation, Research Funds University of Basel, Lichtenstein-Stiftung

Disclosure

All authors have declared no conflicts of interest.