TY - JOUR
T1 - The T-cell receptor repertoire influences the tumor microenvironment and is associated with survival in aggressive B-cell lymphoma
AU - Keane, Colm
AU - Gould, Clare
AU - Jones, Kimberley
AU - Hamm, David
AU - Talaulikar, Dipti
AU - Ellis, Jonathan
AU - Vari, Frank
AU - Birch, Simone
AU - Han, Erica
AU - Wood, Peter
AU - Le-Cao, Kim Anh
AU - Green, Michael R.
AU - Crooks, Pauline
AU - Jain, Sanjiv
AU - Tobin, Josh
AU - Steptoe, Raymond J.
AU - Gandhi, Maher K.
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Purpose: To investigate the relationship between the intratumoral 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 nano-String. 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.
AB - Purpose: To investigate the relationship between the intratumoral 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 nano-String. 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.
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U2 - 10.1158/1078-0432.CCR-16-1576
DO - 10.1158/1078-0432.CCR-16-1576
M3 - Article
C2 - 27649554
AN - SCOPUS:85017007443
SN - 1078-0432
VL - 23
SP - 1820
EP - 1828
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -