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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
Author(s) -
Rieken Johannes,
Bernard Veronica,
Witte Hanno M.,
Peter Wolfgang,
Merz Hartmut,
Olschewski Vito,
Hertel Lars,
Lehnert Hendrik,
Biersack Harald,
Bubnoff Nikolas,
Feller Alfred C.,
Gebauer Niklas
Publication year - 2021
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.17083
Subject(s) - lymphoma , immunology , hazard ratio , biology , t cell receptor , repertoire , oncology , germinal center , medicine , b cell , t cell , confidence interval , antibody , immune system , physics , acoustics
Summary 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 TCRβ 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 = 0·0437) while productive TCR repertoire clonality proved to be a useful indicator of both overall and progression‐free‐survival [OS: P = 0·0001; hazard ratio (HR): 6·220; confidence interval (CI): 2·263–11·78; PFS: P = 0·0025; HR: 3·086; CI: 1·555–7·030]. 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.