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

Abstract

<b>Purpose:</b> To investigate the relationship between the intra-tumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in <i>de novo</i> diffuse large B-cell lymphoma (DLBCL) and the impact of TCR on survival.<b>Experimental Design:</b> 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).<b>Results:</b> The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (<i>P</i> < 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%; <i>P</i> = 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%, <i>P</i> = 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 <i>PD-1, PD-L1</i>, and <i>PD-L2</i> immune checkpoint molecules.<b>Conclusions:</b> 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. <i>Clin Cancer Res; 23(7); 1820-8. ©2016 AACR</i>.