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

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.