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

Thacker, Gatha, Henry, Samantha, Nandi, Ajeya, Debnath, Rahul, Singh, Snahlata, Nayak, Anupma, Susnik, Barbara, Boone, Melinda M, Zhang, Qing, Kesmodel, Susan B, Gumber, Sanjeev, Das, Gokul M, Kambayashi, Taku, Dos Santos, Camila O, Chakrabarti, Rumela (March 2023) Immature natural killer cells promote progression of triple-negative breast cancer. Science Translational Medicine, 15 (686). eabl4414. ISSN 1946-6234

DOI: 10.1126/scitranslmed.abl4414


Natural killer (NK) cells are cytotoxic lymphocytes that accumulate within the tumor microenvironment and are generally considered to be antitumorigenic. Using single-cell RNA sequencing and functional analysis of multiple triple-negative breast cancer (TNBC) and basal tumor samples, we observed a unique subcluster of Socs3highCD11b-CD27- immature NK cells that were present only in TNBC samples. These tumor-infiltrating NK cells expressed a reduced cytotoxic granzyme signature and, in mice, were responsible for activating cancer stem cells through Wnt signaling. NK cell-mediated activation of these cancer stem cells subsequently enhanced tumor progression in mice, whereas depletion of NK cells or Wnt ligand secretion from NK cells by LGK-974 decreased tumor progression. In addition, NK cell depletion or inhibition of their function improved anti-programmed cell death ligand 1 (PD-L1) antibody or chemotherapy response in mice with TNBC. Furthermore, tumor samples from patients with TNBC and non-TNBC revealed that increased numbers of CD56bright NK cells were present in TNBC tumors and were correlated to poor overall survival in patients with TNBC. Together, our findings identify a population of protumorigenic NK cells that may be exploited for both diagnostic and therapeutic strategies to improve outcomes for patients with TNBC.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > breast cancer
Investigative techniques and equipment > assays > RNA-seq
Investigative techniques and equipment > assays > Single cell sequencing
CSHL Authors:
Communities: CSHL labs > Dos Santos lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 8 March 2023
Date Deposited: 17 Mar 2023 15:32
Last Modified: 17 Mar 2023 15:32
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