Exhaustion of tumour-infiltrating T-cell receptor repertoire diversity is an age-dependent indicator of immunological fitness independently predictive of clinical outcome in Burkitt lymphoma

Burkitt lymphoma (BL) is an aggressive B-cell-malignancy derived from germinal-centre B-cells. Curative therapy traditionally requires intensive immunochemotherapy. Recently, immuno-oncological approaches, modulating the T-cell tumour response, were approved for the treatment of a variety of malignancies. The architecture of the tumour-infiltrating T-cell receptor (TCR) repertoire in BL remains insufficiently characterized. We therefore performed a large-scale, next-generation sequencing study of the complimentary-determining region (CDR)-3 region of the TCR beta chain repertoire in a large cohort of all epidemiological subtypes of BL (n = 82) and diffuse large B-cell lymphoma (DLBCL;n = 34). Molecular data were subsequently assessed for correlation with clinical outcome. Our investigations revealed an age-dependent immunoprofile in BL as in DLBCL. Moreover, we found several public clonotypes in numerous patients suggestive of shared tumour neoantigen selection exclusive to BL and distinct from DLBCL regardless of Epstein-Barr virus and/or human immunodeficiency virus status. Compared with baseline, longitudinal analysis unveiled significant repertoire restrictions upon relapse (P = 0 center dot 0437) while productive TCR repertoire clonality proved to be a useful indicator of both overall and progression-free-survival [OS:P = 0 center dot 0001; hazard ratio (HR): 6 center dot 220; confidence interval (CI): 2 center dot 263-11 center dot 78; PFS:P = 0 center dot 0025; HR: 3 center dot 086; CI: 1 center dot 555-7 center dot 030]. Multivariate analysis confirmed its independence from established prognosticators, including age at diagnosis and comorbidities. Our findings establish the clinical relevance of the architecture and clonality of the TCR repertoire and its age-determined dynamics in BL.

Automated summary

The study conducted a large-scale sequencing analysis of the T-cell receptor repertoire in Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), revealing different immune profiles and age-dependent dynamics in BL. Longitudinal analysis showed significant repertoire restrictions upon relapse, with TCR repertoire clonality proving to be an indicator of survival rates.