Immature natural killer cells promote progression of triple-negative breast cancer

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Natural Killer (NK) cells are immune cells typically associated with anti-tumor activity.
• The tumor microenvironment in triple-negative breast cancer (TNBC) harbors complex immune cell populations.
• The specific role of NK cells in TNBC progression is not fully understood.

Purpose of the Study:

• To identify and characterize novel NK cell subsets within the TNBC tumor microenvironment.
• To investigate the functional role of these NK cell subsets in TNBC progression.
• To explore potential therapeutic strategies targeting these NK cells.

Main Methods:

• Single-cell RNA sequencing and functional assays were performed on TNBC and basal tumor samples.
• In vivo studies in mice were used to assess tumor progression and therapeutic interventions.
• Analysis of human TNBC patient tumor samples was conducted.

Main Results:

• A unique subcluster of immature, Socs3^highCD11b^-CD27^- NK cells was identified exclusively in TNBC.
• These tumor-infiltrating NK cells exhibited reduced cytotoxic potential and activated cancer stem cells via Wnt signaling, promoting tumor growth in mice.
• Depletion of these NK cells or inhibition of Wnt signaling reduced tumor progression.
• NK cell depletion or functional inhibition improved responses to anti-PD-L1 therapy and chemotherapy in TNBC models.
• Increased CD56^bright NK cells in TNBC tumors correlated with poor patient survival.

Conclusions:

• A protumorigenic population of NK cells exists in TNBC, characterized by immature phenotype and Wnt signaling activation.
• These findings reveal a novel mechanism of NK cell-mediated tumor promotion in TNBC.
• Targeting this specific NK cell subset offers potential diagnostic and therapeutic avenues for improving outcomes in TNBC patients.