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

Our plain-English summary of T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma, by H. Vroman, G. Balzaretti, R.A. Belderbos, et al (Journal for Immunotherapy of Cancer, 2020).

The study

• Authors: H. Vroman, G. Balzaretti, R.A. Belderbos, P.L. Klarenbeek, M. van Nimwegen, K. Bezemer, R. Cornelissen, I.T.G. Niewold, B.D. van Schaik, A.H. van Kampen, J.G.J.V. Aerts, N. de Vries, R.W. Hendriks
• Journal: Journal for Immunotherapy of Cancer
• Published: 2020;8(1)
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This short report studied the immune cells of nine patients with malignant pleural mesothelioma (MPM) treated with dendritic cell (DC) immunotherapy. In this treatment, the patients' own dendritic cells were loaded with material from laboratory-grown mesothelioma cell lines. The study did not examine asbestos exposure. The authors sequenced T cell receptors in blood taken before and 5 weeks after the start of treatment, and matched T cell 'clones' across samples by their unique receptor sequences. Before treatment, larger average clone sizes among all T cells were correlated with longer overall survival (p=0.0186) and longer progression-free survival (p=0.0227). This correlation was not seen after treatment. Treatment mainly changed a group of cells called PD1+CD8+ T cells. The number of expanding PD1+CD8+ clones correlated with overall survival, progression-free survival and change in tumor volume at about 6 weeks. Expanding PD1+CD4+ clones did not. The authors concluded that this profiling could serve as a predictive biomarker for response to immunotherapy. Because few patients were studied, they said the findings need to be confirmed in a larger, independent group.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Short report: laboratory analysis (T cell receptor beta-chain sequencing) of blood samples taken before and after dendritic cell immunotherapy, compared with clinical outcomes
• Who was studied: Nine patients with malignant pleural mesothelioma (MPM) who received dendritic cell immunotherapy. Blood was sampled before and 5 weeks after the start of therapy. The article text does not state where or when the patients were treated; the authors are based in Rotterdam and Amsterdam, the Netherlands.
• Exposure: No asbestos exposure was studied. The exposure was dendritic cell immunotherapy: the patients' own (autologous) dendritic cells were loaded with tumor lysate from cultured human MPM cell lines (allogeneic).
• Main results:
  • T cell receptor clones in the total CD3+ T cells were matched to those in the sorted T cell subpopulations using their unique CDR3 sequences.
  • In total CD3+ T cells before therapy, average T cell receptor clone size was positively correlated with overall survival (p=0.0186; r2=0.57) and with progression-free survival (p=0.0227; r2=0.52).
  • This positive correlation with clone size in total CD3+ T cells was not observed after therapy.
  • In PD1+CD8+ T cells after therapy, the number of highly expanded clones significantly decreased, and the impact of the most dominant clone increased.
  • The number of expanding PD1+CD8+ T cell clones after therapy correlated with overall survival (p=0.0441; r2=0.4616), with progression-free survival (p=0.0041; r2=0.7152) and with radiographic change in tumor volume at about 6 weeks (p=0.0351; r2=0.4924).
  • No such correlations were seen for the number of expanding PD1+CD4+ T cell clones or for Tregs.
  • Conversion from PD1-negative to PD1-positive, or the reverse, was significantly more frequent in CD8+ than in CD4+ T cells. About 2.7% of new PD1+CD4+ clones and about 10% of new PD1+CD8+ clones had been found as PD1-negative before therapy.
  • Across the nine patients, no expanded clones were shared, and 13 newly appearing clones were shared.
• The authors' conclusion: The authors concluded that T cell receptor repertoire profiling, in both total CD3+ T cells and sorted T cell subsets, could serve as a predictive biomarker for clinical response to immunotherapy in MPM patients.
• Limitations the authors state:
  • Only a small number of patients were analyzed, so the findings need to be validated in a larger, independent dendritic cell therapy cohort.
  • Larger studies are needed to show which of the two measures (pre-treatment clone size or expanding PD1+CD8+ clones) correlates best with clinical outcome.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Immunotherapy, Mesothelioma, Pleural Mesothelioma, Biomarker, Overall Survival, Progression-Free Survival.

Related studies

• Dendritic cell-based immunotherapy in mesothelioma — R. Cornelissen, L.A. Lievense, et al. (2012)
• Serum soluble mesothelin-related protein (SMRP) and fibulin-3 levels correlate with baseline malignant pleural mesothelioma (MPM) tumor volumes but are not useful as biomarkers of response in an immunotherapy trial — S.I. Katz, L. Roshkovan, et al. (2021)
• Malignant mesothelioma clinical trial combines immunotherapy drugs — M.S. Chatwal, T. Tanvetyanon (2018)
• Expression of the T cell receptor Vbeta repertoire in a human T cell resistant to asbestos-induced apoptosis and peripheral blood T cells from patients with silica and asbestos-related diseases — Y. Nishimura, Y. Miura, et al. (2006)
• Adjuvant dendritic cell based immunotherapy (DCBI) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma, a phase II single centre open-label clinical trial: rationale and design of the MESOPEC trial — N.L. de Boer, J.P. van Kooten, et al. (2019)
• New roads open up for implementing immunotherapy in mesothelioma — R. Cornelissen, M.E. Heuvers, et al. (2012)

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