Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients
Abstract Background The combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulat...
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Wiley
2021-06-01
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Series: | Clinical and Translational Medicine |
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Online Access: | https://doi.org/10.1002/ctm2.434 |
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doaj-d78d15107286485db70ae3a5cc239824 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Darawan Rinchai Elena Verzoni Veronica Huber Agata Cova Paola Squarcina Loris De Cecco Filippo deBraud Raffaele Ratta Matteo Dugo Luca Lalli Viviana Vallacchi Monica Rodolfo Jessica Roelands Chiara Castelli Damien Chaussabel Giuseppe Procopio Davide Bedognetti Licia Rivoltini |
spellingShingle |
Darawan Rinchai Elena Verzoni Veronica Huber Agata Cova Paola Squarcina Loris De Cecco Filippo deBraud Raffaele Ratta Matteo Dugo Luca Lalli Viviana Vallacchi Monica Rodolfo Jessica Roelands Chiara Castelli Damien Chaussabel Giuseppe Procopio Davide Bedognetti Licia Rivoltini Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients Clinical and Translational Medicine antiangiogenics bioinformatics blood transcriptomic profile cancer biomarkers immunomonitoring immunosuppression |
author_facet |
Darawan Rinchai Elena Verzoni Veronica Huber Agata Cova Paola Squarcina Loris De Cecco Filippo deBraud Raffaele Ratta Matteo Dugo Luca Lalli Viviana Vallacchi Monica Rodolfo Jessica Roelands Chiara Castelli Damien Chaussabel Giuseppe Procopio Davide Bedognetti Licia Rivoltini |
author_sort |
Darawan Rinchai |
title |
Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients |
title_short |
Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients |
title_full |
Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients |
title_fullStr |
Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients |
title_full_unstemmed |
Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients |
title_sort |
integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients |
publisher |
Wiley |
series |
Clinical and Translational Medicine |
issn |
2001-1326 |
publishDate |
2021-06-01 |
description |
Abstract Background The combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms. Methods We used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571) to assess the prognostic implications of our findings. The effect of pazopanib was assessed in vitro on NK cells and T cells. Additionally, myeloid‐derived suppressor (MDSC)‐like cells were generated from CD14+ monocytes transfected with mimics of miRNAs associated with MDSC function in the presence or absence of pazopanib. Results Pazopanib administration caused a rapid and dramatic reshaping in terms of frequency and transcriptional activity of multiple blood immune cell subsets, with a downsizing of MDSC and regulatory T cells in favor of a strong enhancement in PD‐1 expressing cytotoxic T and Natural Killer effectors. These changes were paired with an increase of the expression of transcripts reflecting activation of immune‐effector functions. This immunomodulation was marked but transient, peaking at the third month of treatment. Moreover, the intratumoral expression level of a MDSC signature (MDSC INT) was strongly associated with poor prognosis in RCC patients. In vitro experiments indicate that the observed immunomodulation might be due to an inhibitory effect on MDSC‐mediated suppression, rather than a direct effect on NK and T cells. Conclusions The marked but transient nature of this immunomodulation, peaking at the third month of treatment, provides the rationale for the use of antiangiogenics as a preconditioning strategy to improve the efficacy of ICB. |
topic |
antiangiogenics bioinformatics blood transcriptomic profile cancer biomarkers immunomonitoring immunosuppression |
url |
https://doi.org/10.1002/ctm2.434 |
work_keys_str_mv |
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doaj-d78d15107286485db70ae3a5cc2398242021-07-13T11:05:29ZengWileyClinical and Translational Medicine2001-13262021-06-01116n/an/a10.1002/ctm2.434Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patientsDarawan Rinchai0Elena Verzoni1Veronica Huber2Agata Cova3Paola Squarcina4Loris De Cecco5Filippo deBraud6Raffaele Ratta7Matteo Dugo8Luca Lalli9Viviana Vallacchi10Monica Rodolfo11Jessica Roelands12Chiara Castelli13Damien Chaussabel14Giuseppe Procopio15Davide Bedognetti16Licia Rivoltini17Cancer Research Department Sidra Medicine Doha QatarMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyUnit of Immunotherapy of Human Tumors Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyUnit of Immunotherapy of Human Tumors Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyUnit of Immunotherapy of Human Tumors Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyPlatform of Integrated Biology Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyMedical Oncology Department Hopital Foch Suresnes FrancePlatform of Integrated Biology Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyUnit of Immunotherapy of Human Tumors Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyUnit of Immunotherapy of Human Tumors Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyUnit of Immunotherapy of Human Tumors Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyCancer Research Department Sidra Medicine Doha QatarUnit of Immunotherapy of Human Tumors Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyImmunology Research Department Sidra Medicine Doha QatarMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyCancer Research Department Sidra Medicine Doha QatarUnit of Immunotherapy of Human Tumors Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyAbstract Background The combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms. Methods We used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571) to assess the prognostic implications of our findings. The effect of pazopanib was assessed in vitro on NK cells and T cells. Additionally, myeloid‐derived suppressor (MDSC)‐like cells were generated from CD14+ monocytes transfected with mimics of miRNAs associated with MDSC function in the presence or absence of pazopanib. Results Pazopanib administration caused a rapid and dramatic reshaping in terms of frequency and transcriptional activity of multiple blood immune cell subsets, with a downsizing of MDSC and regulatory T cells in favor of a strong enhancement in PD‐1 expressing cytotoxic T and Natural Killer effectors. These changes were paired with an increase of the expression of transcripts reflecting activation of immune‐effector functions. This immunomodulation was marked but transient, peaking at the third month of treatment. Moreover, the intratumoral expression level of a MDSC signature (MDSC INT) was strongly associated with poor prognosis in RCC patients. In vitro experiments indicate that the observed immunomodulation might be due to an inhibitory effect on MDSC‐mediated suppression, rather than a direct effect on NK and T cells. Conclusions The marked but transient nature of this immunomodulation, peaking at the third month of treatment, provides the rationale for the use of antiangiogenics as a preconditioning strategy to improve the efficacy of ICB.https://doi.org/10.1002/ctm2.434antiangiogenicsbioinformaticsblood transcriptomic profilecancer biomarkersimmunomonitoringimmunosuppression |