T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma

Heleen Vroman, Giulia Balzaretti, Robert A. Belderbos, Paul L. Klarenbeek, Menno van Nimwegen, Koen Bezemer, Robin Cornelissen, Ilse T. G. Niewold, Barbera D. van Schaik, Antione H. van Kampen, Joachim G. J. V. Aerts, Niek de Vries, Rudi W. Hendriks

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20 Citations (Scopus)

Abstract

Background Malignant pleural mesothelioma (MPM) is a highly lethal malignancy in need for new treatment options. Although immunotherapies have been shown to boost a tumor-specific immune response, not all patients respond and prognostic biomarkers are scarce. In this study, we determined the peripheral blood T cell receptor β (TCRβ) chain repertoire of nine MPM patients before and 5 weeks after the start of dendritic cell (DC)-based immunotherapy. Materials and methods We separately profiled PD1 + and PD1-CD4 + and CD8 + T cells, as well as Tregs and analyzed 70 000 TCRβ sequences per patient. Results Strikingly, limited TCRβ repertoire diversity and high average clone sizes in total CD3 + T cells before the start of immunotherapy were associated with a better clinical response. To explore the differences in TCRβ repertoire prior-DC-therapy and post-DC-therapy, for each patient the TCRβ clones present in the total CD3 + T cell fractions were classified into five categories, based on therapy-associated frequency changes: expanding, decreasing, stable, newly appearing and disappearing clones. Subsequently, the presence of these five groups of clones was analyzed in the individual sorted T cell fractions. DC-therapy primarily induced TCRβ repertoire changes in the PD1 + CD4 + and PD1 + CD8 + T cell fractions. In particular, in the PD1 + CD8 + T cell subpopulation we found high frequencies of expanding, decreasing and newly appearing clones. Conversion from a PD1-to a PD1 + phenotype was significantly more frequent in CD8 + T cells than in CD4 + T cells. Hereby, the number of expanding PD1 + CD8 + T cell clones-and not expanding PD1 + CD4 + T cell clones following immunotherapy positively correlated with overall survival, progression-free survival and reduction of tumor volume. Conclusion We conclude that the clinical response to DC-mediated immunotherapy is dependent on both the pre-existing TCRβ repertoire of total CD3 + T cells and on therapy-induced changes, in particular expanding PD1 + CD8 + T cell clones. Therefore, TCRβ repertoire profiling in sorted T cell subsets could serve as predictive biomarker for the selection of MPM patients that benefit from immunotherapy. Trial registration number NCT02395679.
Original languageEnglish
Article numbere000251
JournalJournal for Immunotherapy of Cancer
Volume8
Issue number1
DOIs
Publication statusPublished - 30 Mar 2020

Keywords

  • immunology
  • oncology

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