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

Author:

Thacker Gatha12ORCID,Henry Samantha3,Nandi Ajeya1,Debnath Rahul1ORCID,Singh Snahlata1,Nayak Anupma4ORCID,Susnik Barbara5ORCID,Boone Melinda M6ORCID,Zhang Qing7ORCID,Kesmodel Susan B8ORCID,Gumber Sanjeev9,Das Gokul M10ORCID,Kambayashi Taku11,Dos Santos Camila O.3ORCID,Chakrabarti Rumela12ORCID

Affiliation:

1. Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.

2. Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.

3. Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.

4. Department of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

5. Department of Pathology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

6. Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.

7. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

8. DeWitt Daughtry Family Department of Surgery, Division of Surgical Oncology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.

9. Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.

10. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

11. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

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 Socs3 high CD11b 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 CD56 bright 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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