Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patients
BackgroundMetastatic breast cancer (mBC) is a heterogeneous disease with varying responses to treatments and clinical outcomes, still requiring the identification of reliable predictive biomarkers. In this context, liquid biopsy has emerged as a powerful tool to assess in real-time the evolving land...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.983887/full |
| _version_ | 1818000494427111424 |
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| author | Elena Muraro Fabio Del Ben Matteo Turetta Daniela Cesselli Daniela Cesselli Michela Bulfoni Rita Zamarchi Elisabetta Rossi Elisabetta Rossi Simon Spazzapan Riccardo Dolcetti Riccardo Dolcetti Riccardo Dolcetti Riccardo Dolcetti Agostino Steffan Giulia Brisotto |
| author_facet | Elena Muraro Fabio Del Ben Matteo Turetta Daniela Cesselli Daniela Cesselli Michela Bulfoni Rita Zamarchi Elisabetta Rossi Elisabetta Rossi Simon Spazzapan Riccardo Dolcetti Riccardo Dolcetti Riccardo Dolcetti Riccardo Dolcetti Agostino Steffan Giulia Brisotto |
| author_sort | Elena Muraro |
| collection | DOAJ |
| description | BackgroundMetastatic breast cancer (mBC) is a heterogeneous disease with varying responses to treatments and clinical outcomes, still requiring the identification of reliable predictive biomarkers. In this context, liquid biopsy has emerged as a powerful tool to assess in real-time the evolving landscape of cancer, which is both orchestrated by the metastatic process and immune-surveillance mechanisms. Thus, we investigated circulating tumor cells (CTCs) coupled with peripheral T-cell immunity to uncover their potential clinical relevance in mBC.MethodsA cohort of 20 mBC patients was evaluated, before and one month after starting therapy, through the following liquid biopsy approaches: CTCs enumerated by a metabolism-based assay, T-cell responses against tumor-associated antigens (TAA) characterized by interferon-γ enzyme-linked immunosorbent spot (ELISpot), and the T-cell receptor (TCR) repertoire investigated by a targeted next-generation sequencing technique. TCR repertoire features were characterized by the Morisita’s overlap and the Productive Simpson Clonality indexes, and the TCR richness. Differences between groups were calculated by Fisher’s, Mann-Whitney or Kruskal-Wallis test, as appropriate. Prognostic data analysis was estimated by Kaplan-Meier method.ResultsStratifying patients for their prognostic level of 6 CTCs before therapy, TAA specific T-cell responses were detected only in patients with a low CTC level. By analyzing the TCR repertoire, the highest TCR clonality was observed in the case of CTCs under the cut-off and a positive ELISpot response (p=0.03). Whereas, at follow-up, patients showing a good clinical response coupled with a low number of CTCs were characterized by the most elevated TCR clonality (p<0.05). The detection of CTCs≥6 in at least one time-point was associated with a lower TCR clonality (p=0.02). Intriguingly, by combining overall survival analysis with TCR repertoire, we highlighted a potential prognostic role of the TCR clonality measured at follow-up (p=0.03).ConclusionThese data, whether validated in a larger cohort of patients, suggest that the combined analysis of CTCs and circulating anti-tumor T-cell immunity could represent a valuable immune-oncological biomarker for the liquid biopsy field. The clinical application of this promising tool could improve the management of mBC patients, especially in the setting of immunotherapy, a rising approach for BC treatment requiring reliable predictive biomarkers. |
| first_indexed | 2024-04-14T03:22:19Z |
| format | Article |
| id | doaj.art-040e787fb799494f91c25f50cb0aee9a |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-14T03:22:19Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-040e787fb799494f91c25f50cb0aee9a2022-12-22T02:15:16ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-08-011210.3389/fonc.2022.983887983887Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patientsElena Muraro0Fabio Del Ben1Matteo Turetta2Daniela Cesselli3Daniela Cesselli4Michela Bulfoni5Rita Zamarchi6Elisabetta Rossi7Elisabetta Rossi8Simon Spazzapan9Riccardo Dolcetti10Riccardo Dolcetti11Riccardo Dolcetti12Riccardo Dolcetti13Agostino Steffan14Giulia Brisotto15Immunopathology and Cancer Biomarkers Units, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, ItalyDepartment of Medicine, University of Udine, Udine, ItalyImmunopathology and Cancer Biomarkers Units, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, ItalyDepartment of Medicine, University of Udine, Udine, ItalyInstitute of Pathology, University Hospital of Udine (Azienda sanitaria universitaria Friuli Centrale, ASUFC), Udine, ItalyInstitute of Pathology, University Hospital of Udine (Azienda sanitaria universitaria Friuli Centrale, ASUFC), Udine, ItalyDepartment of Surgery, Oncology & Gastroenterology, University of Padova, Padua, ItalyDepartment of Surgery, Oncology & Gastroenterology, University of Padova, Padua, ItalyVeneto Institute of Oncology IOV - Istituto di Ricovero e Cura a Carattere Scientifico, Padua, ItalyMedical Oncology and Cancer Prevention Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, ItalyPeter MacCallum Cancer Centre, Melbourne, VIC, AustraliaSir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, AustraliaDepartment of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia0The University of Queensland Diamantina Institute, Brisbane, QLD, AustraliaImmunopathology and Cancer Biomarkers Units, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, ItalyImmunopathology and Cancer Biomarkers Units, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, ItalyBackgroundMetastatic breast cancer (mBC) is a heterogeneous disease with varying responses to treatments and clinical outcomes, still requiring the identification of reliable predictive biomarkers. In this context, liquid biopsy has emerged as a powerful tool to assess in real-time the evolving landscape of cancer, which is both orchestrated by the metastatic process and immune-surveillance mechanisms. Thus, we investigated circulating tumor cells (CTCs) coupled with peripheral T-cell immunity to uncover their potential clinical relevance in mBC.MethodsA cohort of 20 mBC patients was evaluated, before and one month after starting therapy, through the following liquid biopsy approaches: CTCs enumerated by a metabolism-based assay, T-cell responses against tumor-associated antigens (TAA) characterized by interferon-γ enzyme-linked immunosorbent spot (ELISpot), and the T-cell receptor (TCR) repertoire investigated by a targeted next-generation sequencing technique. TCR repertoire features were characterized by the Morisita’s overlap and the Productive Simpson Clonality indexes, and the TCR richness. Differences between groups were calculated by Fisher’s, Mann-Whitney or Kruskal-Wallis test, as appropriate. Prognostic data analysis was estimated by Kaplan-Meier method.ResultsStratifying patients for their prognostic level of 6 CTCs before therapy, TAA specific T-cell responses were detected only in patients with a low CTC level. By analyzing the TCR repertoire, the highest TCR clonality was observed in the case of CTCs under the cut-off and a positive ELISpot response (p=0.03). Whereas, at follow-up, patients showing a good clinical response coupled with a low number of CTCs were characterized by the most elevated TCR clonality (p<0.05). The detection of CTCs≥6 in at least one time-point was associated with a lower TCR clonality (p=0.02). Intriguingly, by combining overall survival analysis with TCR repertoire, we highlighted a potential prognostic role of the TCR clonality measured at follow-up (p=0.03).ConclusionThese data, whether validated in a larger cohort of patients, suggest that the combined analysis of CTCs and circulating anti-tumor T-cell immunity could represent a valuable immune-oncological biomarker for the liquid biopsy field. The clinical application of this promising tool could improve the management of mBC patients, especially in the setting of immunotherapy, a rising approach for BC treatment requiring reliable predictive biomarkers.https://www.frontiersin.org/articles/10.3389/fonc.2022.983887/fullmetastatic breast cancer (mbc)liquid biopsycirculating tumor cells (CTCs)anti-tumor T-cellsT-cell receptor (TCR) |
| spellingShingle | Elena Muraro Fabio Del Ben Matteo Turetta Daniela Cesselli Daniela Cesselli Michela Bulfoni Rita Zamarchi Elisabetta Rossi Elisabetta Rossi Simon Spazzapan Riccardo Dolcetti Riccardo Dolcetti Riccardo Dolcetti Riccardo Dolcetti Agostino Steffan Giulia Brisotto Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patients Frontiers in Oncology metastatic breast cancer (mbc) liquid biopsy circulating tumor cells (CTCs) anti-tumor T-cells T-cell receptor (TCR) |
| title | Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patients |
| title_full | Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patients |
| title_fullStr | Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patients |
| title_full_unstemmed | Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patients |
| title_short | Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patients |
| title_sort | clinical relevance of the combined analysis of circulating tumor cells and anti tumor t cell immunity in metastatic breast cancer patients |
| topic | metastatic breast cancer (mbc) liquid biopsy circulating tumor cells (CTCs) anti-tumor T-cells T-cell receptor (TCR) |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.983887/full |
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