The NKG2D axis: an emerging target in cancer immunotherapy

ABSTRACT

Introduction: The immunoreceptor NKG2D belongs to the best-characterized activating receptors of cytotoxic lymphocytes. NKG2D binds to a variety of cell surface glycoproteins distantly related to MHC class I molecules, termed NKG2D ligands (NKG2DL). NKG2DL are inducibly expressed upon cellular stress, viral infection or malignant transformation thus marking ‘stressed’ or ‘harmful’ cells for clearance through NKG2D⁺ lymphocytes. However, certain viruses and many tumors employ various strategies to escape from NKG2D-mediated immunosurveillance.

Areas covered: Expression and regulation of both NKG2D and NKG2DL, especially at sites of immune responses or in the tumor microenvironment, as well as mechanisms of NKG2D escape strategies, as their understanding is key for harnessing the NKG2D/NKG2DL axis for immunotherapy. Studies documenting the importance of the NKG2D/NKG2DL axis for cancer immunosurveillance. Therapeutic approaches targeting the NKG2D/NKG2DL axis in cancer.

Expert opinion: The selective expression of NKG2DL on malignant cells together with the strong activating potency of NKG2D renders the NKG2D/NKG2DL axis a prime target for immunotherapies. Based on a thorough understanding of the NKG2D/NKG2DL system as well as of the most relevant escape strategies of tumors, the diligent and thoughtful design of novel treatment modalities harnessing the NKG2D/NKG2DL axis holds great promise for the future therapy of cancer.

KEYWORDS:

• NKG2D
• MICA
• ULBP
• cytotoxic lymphocytes
• immunotherapy

Article highlights

• NKG2D is a potent activating immunoreceptor expressed by most cytotoxic lymphocytes enabling them to recognize and to destroy tumor cells.

• Ligands of NKG2D (NKG2DL) are frequently expressed by a broad variety of tumor cells, but not by the corresponding ‘healthy’ tissue.

• Tumor-associated expression of NKG2DL and cytotoxic potential of NKG2D⁺ lymphocytes predestine the NKG2D axis for cancer therapy.

• Multiple therapeutic approaches exploit the NKG2D axis for tumor targeting in various ways including recruitment of NKG2D⁺ cells to tumors, enhancing expression of NKG2D on lymphocytes and/or NKG2DL on tumors, treatment with NKG2D-CAR-expressing lymphocytes or directly targeting NKG2DL-expressing tumor cells.

A major obstacle in harnessing the NKG2D axis for tumor therapy are mechanisms of tumor escape from NKG2D-mediated immunosurveillance such as proteolytic shedding of NKG2DL which can be suppressed by therapeutic antibodies.

Declaration of interest

M.L. declares no conflict of interest. A.S. discloses financial interests in the subject matter due to collaborations with Innate Pharma, Marseille, France, and PDI Therapeutics, La Jolla, USA.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was funded by institutional funds of the Institute for Molecular Medicine.