CDK4/6 inhibition sensitizes breast cancer to NK cell therapy by inducing immune-interactive surface proteins

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are standard treatments for metastatic ER+ breast cancer, but resistance is a major challenge.
• The impact of CDK4/6 inhibitors on innate immune responses, particularly Natural Killer (NK) cells, is not well understood.

Purpose of the Study:

• To investigate how CDK4/6 inhibitors modulate the tumor cell surface and influence NK cell recognition and elimination.
• To explore the potential of combining CDK4/6 inhibitors with NK cell therapy to overcome treatment resistance.

Main Methods:

• Utilized patient-derived organoids (PDOs) and patient-derived xenograft (PDX) models of ER+ breast cancer.
• Assessed changes in cell surface molecules (ICAM-1, NKG2D ligands) following CDK4/6 inhibition.
• Investigated the role of NF-κB and PI3K/mTOR signaling pathways.
• Performed functional assays with NK cells and conducted in vivo studies with abemaciclib and NK cell therapy.

Main Results:

• CDK4/6 inhibition upregulated ICAM-1 and NKG2D stress ligands (ULBP2/5/6, MICA/B) on tumor cells.
• NF-κB and PI3K/mTOR pathways mediated the upregulation of these NK-engaging molecules.
• Upregulated ligands were essential for NK cell-mediated tumor cell killing.
• A short priming treatment with abemaciclib sensitized tumors to NK cell therapy, inhibiting growth and prolonging survival in vivo.
• Concurrent dosing delayed acquired resistance.

Conclusions:

• CDK4/6 inhibitors remodel the tumor cell surface to enhance NK cell recognition and elimination.
• Combining CDK4/6 inhibitors with NK cell therapy, via a "prime and kill" strategy, offers a promising approach to overcome resistance in metastatic ER+ breast cancer.