Large B-cell lymphoma imprints a dysfunctional immune phenotype that persists years after treatment
Abstract
Abstract Immunotherapy has become standard of care in the treatment of diffuse large B-cell lymphoma (DLBCL). Changes in immunophenotypes observed at first diagnosis predict therapy outcome but little is known about the resolution of these alterations in remission. Comprehensive characterization of immune changes from fresh, peripheral whole blood revealed a functionally relevant increase of myeloid-derived suppressor cells, reduced naïve T cells, and an increase of activated and terminally differentiated T cells before treatment, which aggravated after therapy. Suggesting causal relation, injection of lymphoma in mice induced similar changes in the murine T cells. Distinct immune imprints were found in those who have survived breast cancer and acute myeloid leukemia. Identified alterations persisted beyond 5 years of ongoing complete remission and correlated with increased proinflammatory markers such as interleukin-6, β2-microglobulin, or soluble CD14 in DLBCL. The chronic inflammation was associated with functionally blunted T-cell immunity against severe acute respiratory syndrome coronavirus 2–specific peptides, and reduced responses correlated with reduced naïve T cells. Persisting inflammation was confirmed by deep sequencing and by cytokine profiles, together pointing toward a compensatory activation of innate immunity. The persisting, lymphoma-induced immune alterations in remission may explain long-term complications, have implications for vaccine strategies, and are likely relevant for immunotherapies.
Article Details
Authors (28)
Richard J. Pelzl
1Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen and University Hospital Erlangen, Erlangen, Germany
Giulia Benintende
1Department of Internal Medicine 5 - Hematology & Oncology, University Hospital of Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, Medicine 5, Erlangen, Germany
Franziska Gsottberger
Julia K. Scholz
1Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen and University Hospital Erlangen, Erlangen, Germany
Matthias Ruebner
Hao Yao
Kerstin Wendland
1Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen and University Hospital Erlangen, Erlangen, Germany
Kai Rejeski
Memorial Sloan Kettering Cancer Center, New York, New York, United States
Heidi Altmann
Srdjan Petkovic
1Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen and University Hospital Erlangen, Erlangen, Germany
Lisa Mellenthin
1Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen and University Hospital Erlangen, Erlangen, Germany
Sabrina Kübel
10Department of Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen, Erlangen, Germany
Moritz Schmiedeberg
10Department of Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen, Erlangen, Germany
Paulina Klein
10Department of Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen, Erlangen, Germany
Agnese Petrera
Rebecca Baur
1Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen and University Hospital Erlangen, Erlangen, Germany
Sophie Eckstein
2Bavarian Cancer Research Center, Erlangen and Munich, Germany
Sandra Hoepffner-Grundy
12Joint Practice Drs. Hoepffner-Grundy and Kasanmascheff, Erlangen, Germany
Christoph Röllig
22Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany
Marion Subklewe
Ludwig Maximilian University Hospital, Munich, Germany
Hanna Huebner
2Bavarian Cancer Research Center, Erlangen and Munich, Germany
Georg Schett
Friedrich-Alexander-Universität Erlangen–Nürnberg, Erlangen, Germany
Andreas Mackensen
Friedrich-Alexander-Universität Erlangen–Nürnberg, Erlangen, Germany
Luca Laurenti
2Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Agostino Gemelli University Hospital Foundation IRCCS, Rome, Italy
Frederik Graw
Simon Völkl
Friedrich-Alexander-University Erlangen–Nuremberg, Erlangen, Germany
Krystelle Nganou-Makamdop
3Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen and University Hospital Erlangen, Erlangen, Germany
Fabian Müller
Friedrich-Alexander-Universität Erlangen–Nürnberg, Erlangen, Germany