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

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.

Keywords: immunology; oncology.