T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma
Heleen Vroman, G Balzaretti, Robert A. Belderbos, Paul L. Klarenbeek, Menno van Nimwegen, Koen Bezemer, Robin Cornelissen, Ilse T. G. Niewold, Barbera D. C. van Schaik, Antione H van Kampen, Joachim G.J.V. Aerts, Niek de Vries, Rudi W. Hendriks
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 .