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.

Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: relief from immunosuppression is associated with clinical response / Scirocchi, Fabio; Scagnoli, Simone; Botticelli, Andrea; Di Filippo, Alessandra; Napoletano, Chiara; Zizzari, Ilaria Grazia; Strigari, Lidia; Tomao, Silverio; Cortesi, Enrico; Rughetti, Aurelia; Marchetti, Paolo; Nuti, Marianna. - In: EBIOMEDICINE. - ISSN 2352-3964. - 79:(2022). [10.1016/j.ebiom.2022.104010]

Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: relief from immunosuppression is associated with clinical response

Scirocchi, Fabio
Co-primo
;
Scagnoli, Simone
Co-primo
;
Botticelli, Andrea
;
Di Filippo, Alessandra;Napoletano, Chiara;Zizzari, Ilaria Grazia;Strigari, Lidia;Tomao, Silverio;Cortesi, Enrico;Rughetti, Aurelia;Marchetti, Paolo
Co-primo
;
Nuti, Marianna
Co-primo
2022

Abstract

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.
CDK4/6i; regulatory T cells; treg; immune modulation; HR+/HER2- metastatic breast cancer; MDSCs
01 Pubblicazione su rivista::01a Articolo in rivista
Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: relief from immunosuppression is associated with clinical response / Scirocchi, Fabio; Scagnoli, Simone; Botticelli, Andrea; Di Filippo, Alessandra; Napoletano, Chiara; Zizzari, Ilaria Grazia; Strigari, Lidia; Tomao, Silverio; Cortesi, Enrico; Rughetti, Aurelia; Marchetti, Paolo; Nuti, Marianna. - In: EBIOMEDICINE. - ISSN 2352-3964. - 79:(2022). [10.1016/j.ebiom.2022.104010]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1630233
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