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

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.

• Authors: Colm Keane, Clare Gould, Kimberley Jones, David Hamm, Dipti Talaulikar, Jonathan Ellis, Frank Vari, Simone Birch, Erica Han, Peter Wood, Kim-Anh Le-Cao, Michael R Green, Pauline Crooks, Sanjiv Jain, Josh Tobin, Raymond J Steptoe, Maher K Gandhi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 7 Pg. 1820-1828 (Apr 01 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 27649554 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Murine-Derived
• R-CHOP protocol
• Receptors, Antigen, T-Cell, alpha-beta
• Rituximab
• Vincristine
• Doxorubicin
• Cyclophosphamide
• Prednisone

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Murine-Derived (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Cyclophosphamide (administration & dosage)
• Disease-Free Survival
• Doxorubicin (administration & dosage)
• Female
• High-Throughput Nucleotide Sequencing
• Humans
• Kaplan-Meier Estimate
• Lymphoma, B-Cell (drug therapy, genetics, immunology, pathology)
• Male
• Middle Aged
• Neoplasm Staging
• Prednisone (administration & dosage)
• Prognosis
• Receptors, Antigen, T-Cell, alpha-beta (genetics, immunology)
• Rituximab (administration & dosage)
• Tumor Microenvironment (genetics)
• Vincristine (administration & dosage)