The T-cell receptor repertoire influences the tumor microenvironment and is associated with survival in aggressive B-cell lymphoma

Keane, Colm , Gould, Clare , Jones, Kimberley , Hamm, David, Talaulikar, Dipti, Ellis, Jonathan , Vari, Frank, Birch, Simone, Han, Erica , Wood, Peter, Le-Cao, Kim-Anh, Green, Michael R., Crooks, Pauline , Jain, Sanjiv, Tobin, Josh, Steptoe, Raymond J. and Gandhi, Maher K. (2016) The T-cell receptor repertoire influences the tumor microenvironment and is associated with survival in aggressive B-cell lymphoma. Clinical Cancer Research, 23 7: 1820-1828. doi:10.1158/1078-0432.CCR-16-1576


Author Keane, Colm
Gould, Clare
Jones, Kimberley
Hamm, David
Talaulikar, Dipti
Ellis, Jonathan
Vari, Frank
Birch, Simone
Han, Erica
Wood, Peter
Le-Cao, Kim-Anh
Green, Michael R.
Crooks, Pauline
Jain, Sanjiv
Tobin, Josh
Steptoe, Raymond J.
Gandhi, Maher K.
Title The T-cell receptor repertoire influences the tumor microenvironment and is associated with survival in aggressive B-cell lymphoma
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
1557-3265
Publication date 2016-09-20
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-16-1576
Open Access Status Not yet assessed
Volume 23
Issue 7
Start page 1820
End page 1828
Total pages 9
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Language eng
Formatted 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.
Keyword Intratumoral T-cell receptor (TCR)
Tumor microenvironment (TME)
de novo diffuse large B-cell lymphoma (DLBCL)
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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Created: Thu, 06 Apr 2017, 12:22:59 EST by Kylie Hengst on behalf of Research Strategy and Support (Medicine)