Targeting Cancer Stem Cells with Natural Killer Cell Immunotherapy

ABSTRACT

Introduction: Standard cytoreductive cancer therapy, such as chemotherapy and radiotherapy, are frequently resisted by a small portion of cancer cells with ‘stem-cell’ like properties including quiescence and repopulation. Immunotherapy represents a breakthrough modality for improving oncologic outcomes in cancer patients. Since the success of immunotherapy is not contingent on target cell proliferation, it may also be uniquely suited to address the problem of resistance and repopulation exerted by cancer stem cells (CSCs).

Areas covered: Natural killer (NK) cells have long been known for their ability to reject allogeneic hematopoietic stem cells, and there are increasing data demonstrating that NK cells can selectively identify and lyse CSCs. The authors review the current knowledge of CSCs and NK cells and highlight recent studies that support the concept that NK cells are capable of targeting CSC in solid tumors, especially in the context of combination therapy simultaneously targeting non-CSCs and CSCs.

Expert opinion: Unlike cytotoxic cancer treatments, NK cells can target and eliminate quiescent/non-proliferating cells such as CSCs, and these enigmatic cells are an important source of relapse and metastasis. NK targeting of CSCs represents a novel and potentially high impact method to capitalize on the intrinsic therapeutic potential of NK cells

KEYWORDS:

• ALDH
• cancer stem cells
• CD24
• CD44
• CD133
• MICA/MICB
• natural killer cells

Article highlights

• Cancer stem cells are an important source of resistance to standard anti-cancer therapies and can seed relapse/metastasis.

• Natural killer cells are innate lymphoid cells which can kill tumor cells in an MHC-unrestricted fashion.

• Unlike cytotoxic cancer treatments, natural killer cells are able to target and eliminate quiescent/non-proliferating cells such as cancer stem cells.

• Chemotherapy and radiation therapy eliminate non-cancer stem cells, leading to enrichment of cancer stem cells.

• Cancer stem cells upregulate natural killer cell ligands, such as MICA and MICB, after treatment which has been observed to increase natural killer cell targeting of these cells.

• Cancer stem cells also are able to utilize immune evasion strategies such as shedding of MICA and MICB to reduce natural killer cytotoxicity.

• Monoclonal antibodies specific for cancer stem cell epitopes can increase natural killer killing through antibody-dependent cellular cytotoxicity mechanisms.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by funding from the National Institutes of Health (R01CA189209, to WJ Murphy) and the University of California Coordinating Committee for Cancer Control (to RJ Canter).