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

PMID: 32234848
Journal: Journal for immunotherapy of cancer (volume: 8, issue: 1, J Immunother Cancer 2020 Mar;8(1))
Published: 2020-03-01

Vroman H, Balzaretti G, Belderbos RA, Klarenbeek PL, van Nimwegen M, Bezemer K, Cornelissen R, Niewold ITG, van Schaik BD, van Kampen AH, Aerts JGJV, de Vries N, Hendriks RW


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 PD1CD4 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 PD1CD4 and PD1CD8 T cell fractions. In particular, in the PD1CD8 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 PD1CD8 T cell clones-and not expanding PD1CD4 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 PD1CD8 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.