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
Abstract
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 diseases & disorders Investigative techniques and equipment diseases & disorders > neoplasms organism description > animal Investigative techniques and equipment > assays diseases & disorders > cancer > cancer types > breast cancer organism description > animal > mammal organism description > animal > mammal > rodent > mouse Investigative techniques and equipment > assays > RNA-seq organism description > animal > mammal > rodent Investigative techniques and equipment > assays > Single cell sequencing diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Dos Santos lab CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 8 March 2023 |
| Date Deposited: | 17 Mar 2023 15:32 |
| Last Modified: | 30 Apr 2024 13:20 |
| PMCID: | PMC10875969 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/40860 |
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