Petros Christopoulos1, Marc A Schneider2, Farastuk Bozorgmehr3, Jonas Kuon3, Walburga Engel-Riedel4, Jens Kollmeier5, Volker Baum6, Thomas Muley2, Philipp A Schnabel7, Helge Bischoff8, Christian Grohé9, Monika Serke10, Michael Thomas11, Paul Fisch12, Michael Meister2. 1. Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Member of the German Center for Lung Research (DZL), Germany. Electronic address: petros.christopoulos@med.uni-heidelberg.de. 2. Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Member of the German Center for Lung Research (DZL), Germany. 3. Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Member of the German Center for Lung Research (DZL), Germany. 4. Department of Pneumology, Lung Hospital Cologne Merheim, City of Cologne Municipal Hospitals, Cologne, Germany. 5. Department of Pneumology, HELIOS Hospital Emil von Behring, Berlin, Germany. 6. Business Unit Oncology, Novartis Pharma GmbH, Nürnberg, Germany. 7. Department of Pathology, University Medical Center Saarland, Homburg, Germany. 8. Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Germany. 9. Department of Pneumology, Protestant Lung Hospital Berlin, Germany. 10. Department of Pneumology, Lung Hospital Hemer, Germany. 11. Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Germany; Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Germany. 12. Department of Pathology, Freiburg University Hospital, Freiburg, Germany.
Abstract
OBJECTIVES: This study was performed to evaluate for a potentially important role of T cells in the pathophysiology and treatment sensitivity of large cell neuroendocrine lung carcinoma (LCNEC), an orphan disease with poor prognosis and scarce data to guide novel therapeutic strategies. MATERIALS AND METHODS: We performed T-cell receptor (TCR) β-chain spectratyping on blood samples of patients treated within the CRAD001KDE37 trial (n = 35) using age-matched current or former (n = 11) and never smokers (n = 10) as controls. The data were analyzed in conjunction with the complete blood counts of the probands as well as the data about response to treatment and overall survival in the clinical trial. RESULTS AND CONCLUSION: Untreated stage IV LCNEC patients had significant T-cell repertoire alterations (p < 0.001) compared to age-matched smokers. These changes correlated positively with blood lymphocyte counts (r = 0.49, p < 0.01), suggesting antigen-induced T-cell proliferation as the causative mechanism. At the same time, LCNEC patients showed mild lymphopenia (1.54 vs. 2.51/nl in median, p < 0.01), which reveals a second, antigen-independent mechanism of systemic immune dysregulation. More pronounced T-cell repertoire alterations and higher blood lymphocyte counts at diagnosis were associated with a better treatment response by RECIST and with a longer overall survival (441 vs. 157 days in median, p = 0.019). A higher degree of T-cell repertoire normalization after 3 months of therapy also distinguished a patient group with more favourable prognosis (median overall survival 617 vs. 316 days, p = 0.036) independent of radiological response. Thus, LCNEC induces clinically relevant changes of the T-cell repertoire, which are measurable in the blood and could be exploited for prognostic, predictive and therapeutic purposes. Their pathogenesis appears to involve antigen-induced oligoclonal T-cell expansions superimposed on TCR-independent lymphopenia.
OBJECTIVES: This study was performed to evaluate for a potentially important role of T cells in the pathophysiology and treatment sensitivity of large cell neuroendocrine lung carcinoma (LCNEC), an orphan disease with poor prognosis and scarce data to guide novel therapeutic strategies. MATERIALS AND METHODS: We performed T-cell receptor (TCR) β-chain spectratyping on blood samples of patients treated within the CRAD001KDE37 trial (n = 35) using age-matched current or former (n = 11) and never smokers (n = 10) as controls. The data were analyzed in conjunction with the complete blood counts of the probands as well as the data about response to treatment and overall survival in the clinical trial. RESULTS AND CONCLUSION: Untreated stage IV LCNECpatients had significant T-cell repertoire alterations (p < 0.001) compared to age-matched smokers. These changes correlated positively with blood lymphocyte counts (r = 0.49, p < 0.01), suggesting antigen-induced T-cell proliferation as the causative mechanism. At the same time, LCNECpatients showed mild lymphopenia (1.54 vs. 2.51/nl in median, p < 0.01), which reveals a second, antigen-independent mechanism of systemic immune dysregulation. More pronounced T-cell repertoire alterations and higher blood lymphocyte counts at diagnosis were associated with a better treatment response by RECIST and with a longer overall survival (441 vs. 157 days in median, p = 0.019). A higher degree of T-cell repertoire normalization after 3 months of therapy also distinguished a patient group with more favourable prognosis (median overall survival 617 vs. 316 days, p = 0.036) independent of radiological response. Thus, LCNEC induces clinically relevant changes of the T-cell repertoire, which are measurable in the blood and could be exploited for prognostic, predictive and therapeutic purposes. Their pathogenesis appears to involve antigen-induced oligoclonal T-cell expansions superimposed on TCR-independent lymphopenia.
Authors: Stephan Rheinheimer; Claus-Peter Heussel; Philipp Mayer; Lena Gaissmaier; Farastuk Bozorgmehr; Hauke Winter; Felix J Herth; Thomas Muley; Stephan Liersch; Helge Bischoff; Mark Kriegsmann; Rami A El Shafie; Albrecht Stenzinger; Michael Thomas; Hans-Ulrich Kauczor; Petros Christopoulos Journal: Cancers (Basel) Date: 2020-04-23 Impact factor: 6.639
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Authors: Timothy Rajakumar; Rastislav Horos; Paul Kittner; Mustafa Kahraman; Tobias Sikosek; Franziska Hinkfoth; Kaja Tikk; Nathaniel D Mercaldo; Albrecht Stenzinger; Klaus F Rabe; Martin Reck; Michael Thomas; Petros Christopoulos; Bruno R Steinkraus Journal: JTO Clin Res Rep Date: 2022-06-20
Authors: David Fisch; Farastuk Bozorgmehr; Daniel Kazdal; Jonas Kuon; Laura V Klotz; Rajiv Shah; Florian Eichhorn; Mark Kriegsmann; Marc A Schneider; Thomas Muley; Albrecht Stenzinger; Helge Bischoff; Petros Christopoulos Journal: Front Oncol Date: 2021-07-08 Impact factor: 6.244