T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma. Issue 1 (30th March 2020)

• Record Type: Journal Article
• Authors: Vroman, Heleen; Balzaretti, Giulia; Belderbos, Robert A; Klarenbeek, Paul L; van Nimwegen, Menno; Bezemer, Koen; Cornelissen, Robin; Niewold, Ilse T G; van Schaik, Barbera D; van Kampen, Antione H; Aerts, Joachim G J V; de Vries, Niek; Hendriks, Rudi W
• Is Part Of: Journal for immunotherapy of cancer. Volume 8:Issue 1(2020)
• Publication Date: 2020-03-30
• Subjects: immunology -- oncology; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2019-000251
• Languages: English
• ISSNs: 2051-1426

Abstract

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 .