Cellular interactions within the immune microenvironment underpins resistance to cell cycle inhibition in breast cancers

Jason I. Griffiths (), Patrick A. Cosgrove, Eric F. Medina, Aritro Nath, Jinfeng Chen, Frederick R. Adler, Jeffrey T. Chang, Qamar J. Khan and Andrea H. Bild ()
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Jason I. Griffiths: 1500 East Duarte Road
Patrick A. Cosgrove: 1500 East Duarte Road
Eric F. Medina: 1500 East Duarte Road
Aritro Nath: 1500 East Duarte Road
Jinfeng Chen: 1500 East Duarte Road
Frederick R. Adler: University of Utah 155 South 1400 East
Jeffrey T. Chang: UT Health Sciences Center at Houston
Qamar J. Khan: The University of Kansas Medical Center
Andrea H. Bild: 1500 East Duarte Road

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract Immune evasion by cancer cells involves reshaping the tumor microenvironment (TME) via communication with non-malignant cells. However, resistance-promoting interactions during treatment remain lesser known. Here we examine the composition, communication, and phenotypes of tumor-associated cells in serial biopsies from stage II and III high-risk estrogen receptor positive (ER+ ) breast cancers of patients receiving endocrine therapy (letrozole) as single agent or in combination with ribociclib, a CDK4/6-targeting cell cycle inhibitor. Single-cell RNA sequencing analyses on longitudinally collected samples show that in tumors overcoming the growth suppressive effects of ribociclib, first cancer cells upregulate cytokines and growth factors that stimulate immune-suppressive myeloid differentiation, resulting in reduced myeloid cell- CD8 + T-cell crosstalk via IL-15/18 signaling. Subsequently, tumors growing during treatment show diminished T-cell activation and recruitment. In vitro, ribociclib does not only inhibit cancer cell growth but also T cell proliferation and activation upon co-culturing. Exogenous IL-15 improves CDK4/6 inhibitor efficacy by augmenting T-cell proliferation and cancer cell killing by T cells. In summary, response to ribociclib in stage II and III high-risk ER + breast cancer depends on the composition, activation phenotypes and communication network of immune cells.

Date: 2025
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DOI: 10.1038/s41467-025-56279-x

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