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Clin Cancer Res. 2017 Apr 1;23(7):1820-1828. doi: 10.1158/1078-0432.CCR-16-1576. Epub 2016 Sep 20.

The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma.

Author information

1
University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia. c.keane@uq.edu.au M.Gandhi@uq.edu.au.
2
Princess Alexandra Hospital, Brisbane, Queensland, Australia.
3
University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia.
4
Adaptive Biotechnologies, Seattle, Washington.
5
Canberra Hospital, Canberra, Australian Capital Territory, Australia.
6
Australian National University Medical School, Australian Capital Territory, Australia.
7
Pathology Queensland, Brisbane, Queensland, Australia.
8
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.

Abstract

Purpose: To investigate the relationship between the intra-tumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo diffuse large B-cell lymphoma (DLBCL) and the impact of TCR on survival.Experimental Design: We performed high-throughput unbiased TCRβ sequencing on a population-based cohort of 92 patients with DLBCL treated with conventional (i.e., non-checkpoint blockade) frontline "R-CHOP" therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString. The primary endpoints were 4-year overall survival (OS) and progression-free survival (PFS).Results: The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (P < 0.0001). In DLBCL, a highly dominant single T-cell clone was associated with inferior 4-year OS rate of 60.0% [95% confidence interval (CI), 31.7%-79.6%], compared with 79.8% in patients with a low dominant clone (95% CI, 66.7%-88.5%; P = 0.005). A highly dominant clone also predicted inferior 4-year PFS rate of 46.6% (95% CI, 22.5%-76.6%) versus 72.6% (95% CI, 58.8%-82.4%, P = 0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV+ DLBCL subtype that is known to express immunogenic viral antigens and is associated with particularly poor outcome. Increased T-cell diversity was associated with significantly elevated PD-1, PD-L1, and PD-L2 immune checkpoint molecules.Conclusions: Put together, these findings suggest that the TCR repertoire is a key determinant of the TME. Highly dominant T-cell clonal expansions within the TME are associated with poor outcome in DLBCL treated with conventional frontline therapy. Clin Cancer Res; 23(7); 1820-8. ©2016 AACR.

PMID:
27649554
DOI:
10.1158/1078-0432.CCR-16-1576
[Indexed for MEDLINE]
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