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 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 TCRb 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 ¼ 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 ¼ 0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV þ 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.

The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma

“…19 Furthermore, substantially higher clonal T-cell responses were observed in EBV -pos vs EBV -neg DLBCL. 19 Although the prognostic impact of the TME in de novo DLBCL is well-established, [20][21][22][23][24] it remains untested as to whether the TME is associated with differential survival in EBV -pos DLBCL.…”

A scoring system for the electrostatic complementarities of T‐cell receptors and cancer‐mutant amino acids: multi‐cancer analyses of associated survival rates

“…More recently, several additional tools that have the potential of contributing to a resolution of some of the above issues have become available. First, bioinformatics and computational approaches have made it clear that chemical and structural features of the TCR complementarity‐determining region 3 (CDR3) can correlate with a specific immune response . This development points to the second development, the employment of which offers promise for learning more about specific cancer patient, TCR CDR3, mutant peptide interactions, namely the vast databases now available representing cancer patient mutant amino acids (aa) and tens of thousands of TCR CDR3s for the corresponding TILs.…”

T‐cell receptor diversity as a prognostic biomarker in melanoma patients

“…The diversity of circulating TCR repertoire is gradually decreasing during tumor progression in patients with cervical cancer (Cui et al, ). Elsewhere, high dominant clones within tumor microenvironment were associated with poor outcome in diffuse large B‐cell lymphoma (Keane et al, ).…”