Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients
<h3>Background</h3><p dir="ltr">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...
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| مؤلفون آخرون: | , , , , , , , , , , , , , , , , |
| منشور في: |
2021
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| _version_ | 1864513555831717888 |
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| author | Darawan Rinchai (742366) |
| author2 | Elena Verzoni (725945) Veronica Huber (264942) Agata Cova (8568057) Paola Squarcina (8568060) Loris De Cecco (107073) Filippo Braud (6424019) Raffaele Ratta (14778157) Matteo Dugo (136516) Luca Lalli (9412753) Viviana Vallacchi (7872872) Monica Rodolfo (370777) Jessica Roelands (7516439) Chiara Castelli (5863631) Damien Chaussabel (26369) Giuseppe Procopio (503244) Davide Bedognetti (9471254) Licia Rivoltini (264945) |
| author2_role | author author author author author author author author author author author author author author author author author |
| author_facet | Darawan Rinchai (742366) Elena Verzoni (725945) Veronica Huber (264942) Agata Cova (8568057) Paola Squarcina (8568060) Loris De Cecco (107073) Filippo Braud (6424019) Raffaele Ratta (14778157) Matteo Dugo (136516) Luca Lalli (9412753) Viviana Vallacchi (7872872) Monica Rodolfo (370777) Jessica Roelands (7516439) Chiara Castelli (5863631) Damien Chaussabel (26369) Giuseppe Procopio (503244) Davide Bedognetti (9471254) Licia Rivoltini (264945) |
| author_role | author |
| dc.creator.none.fl_str_mv | Darawan Rinchai (742366) Elena Verzoni (725945) Veronica Huber (264942) Agata Cova (8568057) Paola Squarcina (8568060) Loris De Cecco (107073) Filippo Braud (6424019) Raffaele Ratta (14778157) Matteo Dugo (136516) Luca Lalli (9412753) Viviana Vallacchi (7872872) Monica Rodolfo (370777) Jessica Roelands (7516439) Chiara Castelli (5863631) Damien Chaussabel (26369) Giuseppe Procopio (503244) Davide Bedognetti (9471254) Licia Rivoltini (264945) |
| dc.date.none.fl_str_mv | 2021-06-20T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1002/ctm2.434 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Integrated_transcriptional_phenotypic_analysis_captures_systemic_immunomodulation_following_antiangiogenic_therapy_in_renal_cell_carcinoma_patients/22257994 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Bioinformatics and computational biology Biomedical and clinical sciences Cardiovascular medicine and haematology Immunology Oncology and carcinogenesis antiangiogenics bioinformatics blood transcriptomic profile cancer biomarkers immunomonitoring immunosuppression immunotherapy myeloid-derived suppressor cells pazopanib renal cell carcinoma transcriptional modular repertoire analysis tyrosine kinase inhibitors |
| dc.title.none.fl_str_mv | Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background</h3><p dir="ltr">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.</p><h3>Methods</h3><p dir="ltr">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<sup>+</sup> monocytes transfected with mimics of miRNAs associated with MDSC function in the presence or absence of pazopanib.</p><h3>Results</h3><p dir="ltr">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.</p><h3>Conclusions</h3><p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Clinical and Translational Medicine<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1002/ctm2.434" target="_blank">http://dx.doi.org/10.1002/ctm2.434</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_022d71a5823a52262c1615fe4e4543c0 |
| identifier_str_mv | 10.1002/ctm2.434 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/22257994 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patientsDarawan Rinchai (742366)Elena Verzoni (725945)Veronica Huber (264942)Agata Cova (8568057)Paola Squarcina (8568060)Loris De Cecco (107073)Filippo Braud (6424019)Raffaele Ratta (14778157)Matteo Dugo (136516)Luca Lalli (9412753)Viviana Vallacchi (7872872)Monica Rodolfo (370777)Jessica Roelands (7516439)Chiara Castelli (5863631)Damien Chaussabel (26369)Giuseppe Procopio (503244)Davide Bedognetti (9471254)Licia Rivoltini (264945)Biological sciencesBioinformatics and computational biologyBiomedical and clinical sciencesCardiovascular medicine and haematologyImmunologyOncology and carcinogenesisantiangiogenicsbioinformaticsblood transcriptomic profilecancer biomarkersimmunomonitoringimmunosuppressionimmunotherapymyeloid-derived suppressor cellspazopanibrenal cell carcinomatranscriptional modular repertoire analysistyrosine kinase inhibitors<h3>Background</h3><p dir="ltr">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.</p><h3>Methods</h3><p dir="ltr">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<sup>+</sup> monocytes transfected with mimics of miRNAs associated with MDSC function in the presence or absence of pazopanib.</p><h3>Results</h3><p dir="ltr">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.</p><h3>Conclusions</h3><p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Clinical and Translational Medicine<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1002/ctm2.434" target="_blank">http://dx.doi.org/10.1002/ctm2.434</a></p>2021-06-20T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1002/ctm2.434https://figshare.com/articles/journal_contribution/Integrated_transcriptional_phenotypic_analysis_captures_systemic_immunomodulation_following_antiangiogenic_therapy_in_renal_cell_carcinoma_patients/22257994CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/222579942021-06-20T09:00:00Z |
| spellingShingle | Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients Darawan Rinchai (742366) Biological sciences Bioinformatics and computational biology Biomedical and clinical sciences Cardiovascular medicine and haematology Immunology Oncology and carcinogenesis antiangiogenics bioinformatics blood transcriptomic profile cancer biomarkers immunomonitoring immunosuppression immunotherapy myeloid-derived suppressor cells pazopanib renal cell carcinoma transcriptional modular repertoire analysis tyrosine kinase inhibitors |
| status_str | publishedVersion |
| title | 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_short | 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 |
| topic | Biological sciences Bioinformatics and computational biology Biomedical and clinical sciences Cardiovascular medicine and haematology Immunology Oncology and carcinogenesis antiangiogenics bioinformatics blood transcriptomic profile cancer biomarkers immunomonitoring immunosuppression immunotherapy myeloid-derived suppressor cells pazopanib renal cell carcinoma transcriptional modular repertoire analysis tyrosine kinase inhibitors |