Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: Relief from immunosuppression is associated with clinical response
Summary: Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are innovative small target molecules that, in combination with endocrine therapy, have recently been employed in the treatment of patients with HR+/HER2− metastatic breast cancer (mBC). In this prospective study, we investigate...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-05-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396422001943 |
| _version_ | 1818274715857321984 |
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| author | Fabio Scirocchi Simone Scagnoli Andrea Botticelli Alessandra Di Filippo Chiara Napoletano Ilaria Grazia Zizzari Lidia Strigari Silverio Tomao Enrico Cortesi Aurelia Rughetti Paolo Marchetti Marianna Nuti |
| author_facet | Fabio Scirocchi Simone Scagnoli Andrea Botticelli Alessandra Di Filippo Chiara Napoletano Ilaria Grazia Zizzari Lidia Strigari Silverio Tomao Enrico Cortesi Aurelia Rughetti Paolo Marchetti Marianna Nuti |
| author_sort | Fabio Scirocchi |
| collection | DOAJ |
| description | Summary: Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are innovative small target molecules that, in combination with endocrine therapy, have recently been employed in the treatment of patients with HR+/HER2− metastatic breast cancer (mBC). In this prospective study, we investigate the impact of CDK4/6i on the immune profile of patients with HR+/HER2− mBC. Methods: Immune cell subsets were analysed using flow cytometry of peripheral blood mononuclear cells (PBMCs) isolated from patients with HR+/HER2− mBC, both before and during treatment. Regulatory T cells (Tregs) were identified using the markers CD4, CD25, CTLA4, CD45RA, and intracellular FOXP3. Monocytic and polymorphonuclear myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs) and other immune populations were analysed using CD45, CD14, CD66b, CD11c, HLA-DR, CD3, CD8, CD28, CD137, PD1, CD45RA, CCR7, and Ki67. Findings: The percentage of circulating Tregs and M/PMN-MDSCs was significantly downregulated from baseline during CDK4/6i-treatment (p<0.0001 and p<0.05, respectively). In particular, the effector Treg subset (CD4+CD25+FOXP3highCD45RA−) was strongly reduced (p<0.0001). The decrease in Treg levels was significantly greater in responder patients than in non-responder patients. Conversely, CDK4/6i treatment was associated with increased levels of CD4+ T cells and anti-tumour CD137+CD8+ T cells (p<0.05). Interpretation: CDK4/6i treatment results in downregulation of Tregs, M-MDSCs, and PMN-MDSCs, thus weakening tumour immunosuppression. This decrease is associated with response to treatment, highlighting the importance of unleashing immunity in cancer treatment efficacy. These results suggest a novel mechanism of immunomodulation in mBC and provide valuable information for the future design of novel treatments combining CDK4/6i with immunotherapy in other cancer settings. Funding: Sapienza University of Rome. |
| first_indexed | 2024-12-12T22:18:16Z |
| format | Article |
| id | doaj.art-91e990b21f784fe680b1ad00938ec62e |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-12T22:18:16Z |
| publishDate | 2022-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-91e990b21f784fe680b1ad00938ec62e2022-12-22T00:10:01ZengElsevierEBioMedicine2352-39642022-05-0179104010Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: Relief from immunosuppression is associated with clinical responseFabio Scirocchi0Simone Scagnoli1Andrea Botticelli2Alessandra Di Filippo3Chiara Napoletano4Ilaria Grazia Zizzari5Lidia Strigari6Silverio Tomao7Enrico Cortesi8Aurelia Rughetti9Paolo Marchetti10Marianna Nuti11Department of Experimental Medicine, Laboratory of Tumor Immunology and Cell Therapy, Sapienza University of Rome, Rome 00161, ItalyDepartment of Medical and Surgical Sciences and Translational Medicine, Sapienza University of Rome, Rome 00185, ItalyDepartment of Radiology, Oncology and Human Pathology, Policlinico Umberto I ''Sapienza'' University of Rome, Rome 00185, Italy; Corresponding author.Department of Experimental Medicine, Laboratory of Tumor Immunology and Cell Therapy, Sapienza University of Rome, Rome 00161, ItalyDepartment of Experimental Medicine, Laboratory of Tumor Immunology and Cell Therapy, Sapienza University of Rome, Rome 00161, ItalyDepartment of Experimental Medicine, Laboratory of Tumor Immunology and Cell Therapy, Sapienza University of Rome, Rome 00161, ItalyMedical Physics Unit, “S. Orsola-Malpighi” Hospital, Bologna, ItalyDepartment of Radiology, Oncology and Human Pathology, Policlinico Umberto I ''Sapienza'' University of Rome, Rome 00185, ItalyDepartment of Radiology, Oncology and Human Pathology, Policlinico Umberto I ''Sapienza'' University of Rome, Rome 00185, ItalyDepartment of Experimental Medicine, Laboratory of Tumor Immunology and Cell Therapy, Sapienza University of Rome, Rome 00161, ItalyIDI-IRCCS, Via Monti di Creta 104, 00167 Roma, ItalyDepartment of Experimental Medicine, Laboratory of Tumor Immunology and Cell Therapy, Sapienza University of Rome, Rome 00161, ItalySummary: Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are innovative small target molecules that, in combination with endocrine therapy, have recently been employed in the treatment of patients with HR+/HER2− metastatic breast cancer (mBC). In this prospective study, we investigate the impact of CDK4/6i on the immune profile of patients with HR+/HER2− mBC. Methods: Immune cell subsets were analysed using flow cytometry of peripheral blood mononuclear cells (PBMCs) isolated from patients with HR+/HER2− mBC, both before and during treatment. Regulatory T cells (Tregs) were identified using the markers CD4, CD25, CTLA4, CD45RA, and intracellular FOXP3. Monocytic and polymorphonuclear myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs) and other immune populations were analysed using CD45, CD14, CD66b, CD11c, HLA-DR, CD3, CD8, CD28, CD137, PD1, CD45RA, CCR7, and Ki67. Findings: The percentage of circulating Tregs and M/PMN-MDSCs was significantly downregulated from baseline during CDK4/6i-treatment (p<0.0001 and p<0.05, respectively). In particular, the effector Treg subset (CD4+CD25+FOXP3highCD45RA−) was strongly reduced (p<0.0001). The decrease in Treg levels was significantly greater in responder patients than in non-responder patients. Conversely, CDK4/6i treatment was associated with increased levels of CD4+ T cells and anti-tumour CD137+CD8+ T cells (p<0.05). Interpretation: CDK4/6i treatment results in downregulation of Tregs, M-MDSCs, and PMN-MDSCs, thus weakening tumour immunosuppression. This decrease is associated with response to treatment, highlighting the importance of unleashing immunity in cancer treatment efficacy. These results suggest a novel mechanism of immunomodulation in mBC and provide valuable information for the future design of novel treatments combining CDK4/6i with immunotherapy in other cancer settings. Funding: Sapienza University of Rome.http://www.sciencedirect.com/science/article/pii/S2352396422001943CDK4/6iRegulatory T cellsTregImmune modulationHR+/HER2- metastatic breast cancerMDSCs |
| spellingShingle | Fabio Scirocchi Simone Scagnoli Andrea Botticelli Alessandra Di Filippo Chiara Napoletano Ilaria Grazia Zizzari Lidia Strigari Silverio Tomao Enrico Cortesi Aurelia Rughetti Paolo Marchetti Marianna Nuti Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: Relief from immunosuppression is associated with clinical response EBioMedicine CDK4/6i Regulatory T cells Treg Immune modulation HR+/HER2- metastatic breast cancer MDSCs |
| title | Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: Relief from immunosuppression is associated with clinical response |
| title_full | Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: Relief from immunosuppression is associated with clinical response |
| title_fullStr | Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: Relief from immunosuppression is associated with clinical response |
| title_full_unstemmed | Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: Relief from immunosuppression is associated with clinical response |
| title_short | Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: Relief from immunosuppression is associated with clinical response |
| title_sort | immune effects of cdk4 6 inhibitors in patients with hr her2 metastatic breast cancer relief from immunosuppression is associated with clinical response |
| topic | CDK4/6i Regulatory T cells Treg Immune modulation HR+/HER2- metastatic breast cancer MDSCs |
| url | http://www.sciencedirect.com/science/article/pii/S2352396422001943 |
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