Editors' ChoiceCancer Immunotherapy

NK cells set sights on cancer stem cells

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Science Translational Medicine  23 Sep 2015:
Vol. 7, Issue 306, pp. 306ec160
DOI: 10.1126/scitranslmed.aad3617

In the quest for effective new immunotherapies, one cell population continues to be resistant: cancer stem cells (CSCs). CSCs don’t respond to traditional therapies and are often responsible for tumor repopulation and metastasis. These cells have long been elusive, with only recent characterization of reliable markers that may differ by primary tumor site. A new study by Ames et al. demonstrates that NK cells may preferentially target CSCs by virtue of their natural ability to home to nondividing cells, in contrast to other cytotoxic cells, which target dividing cells. The authors sorted CSCs aldehyde dehydrogenase 1 (ALDH1) from pancreatic cancer, breast cancer, and sarcoma cell lines. Sorted “bright” cells (high ALDH1 expression) versus “dim” cells were then exposed to NK cells, which promptly killed ALDH1bright cells more effectively than the ALDH1dim ones. This preferential targeting was confirmed with fresh human tumor specimens in single-cell suspension and allogeneic NK cells. To examine mechanism, the authors showed that ALDH1bright cells had greater surface expression of death receptors and of ligands for the NK activation receptor, NKG2D; blocking NKG2D stopped NK cell killing of CSCs. In vivo in mouse xenografts of multiple human cancer cell lines, NK cells colocalized with CSCs in the tumors, suggesting active targeting. Furthermore, the ALDH1bright cell population isolated from the tumors was significantly decreased, while the ALDH1dim cell population remained unchanged in mice that received NK cells. Even ex vivo–activated NK cells administered intravenously to mice with lung and liver metastases led to reduced tumor colonies, suggesting that NK immunotherapy may be an option for controlling metastatic disease. This study raises renewed interest for NK cell immunotherapy to fight notoriously recalcitrant CSCs.

E. Ames et al., NK cells preferentially target tumor cells with a cancer stem cell phenotype, J. Immunol. 10.14049/jimmunol.1500447 (2015). [Abstract]

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