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

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.

• Authors: 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
• Journal: EBioMedicine (EBioMedicine) Vol. 79 Pg. 104010 (May 2022) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 35477069 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Forkhead Transcription Factors
• CDK4 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Breast Neoplasms (pathology)
• CD8-Positive T-Lymphocytes
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• Female
• Forkhead Transcription Factors
• Humans
• Immunosuppression Therapy
• Leukocytes, Mononuclear
• Prospective Studies