Arming cytotoxic lymphocytes for cancer immunotherapy by means of the NKG2D/NKG2D-ligand system

ABSTRACT

Introduction

The activating NKG2D receptor plays a central role in the immune recognition and elimination of abnormal self-cells by cytotoxic lymphocytes. NKG2D binding to cell stress-inducible ligands (NKG2DL) up-regulated on cancer cells facilitates their immunorecognition. Yet tumor cells utilize various escape mechanisms to avert NKG2D-based immunosurveillance. Hence, therapeutic strategies targeting the potent NKG2D/NKG2DL axis and such immune escape mechanisms become increasingly attractive in cancer therapy.

Areas covered

This perspective provides a brief introduction into the NKG2D/NKG2DL axis and its relevance for cancer immune surveillance. Subsequently, the most advanced therapeutic approaches targeting the NKG2D system are presented focusing on NKG2D-CAR engineered immune cells and antibody-mediated strategies to inhibit NKG2DL shedding by tumors.

Expert opinion

Thus far, NKG2D-CAR engineered lymphocytes represent the most advanced therapeutic approach utilizing the NKG2D system. Similarly to other tumor-targeting CAR approaches, NKG2D-CAR cells demonstrate powerful on-target activity, but may also cause off-tumor toxicities or lose efficacy, if NKG2DL expression by tumors is reduced. However, NKG2D-CAR cells also act on the tumor microenvironment curtailing its immunosuppressive properties, thus providing an independent therapeutic benefit. The potency of tumoricidal NKG2D-expressing lymphocytes can be further boosted by enhancing NKG2DL expression through small molecules and therapeutic antibodies inhibiting tumor-associated shedding of NKG2DL.

KEYWORDS:

• Cancer
• immunotherapy
• NKG2D
• MICA
• ULBP
• CAR
• NK cell
• t cell
• lymphocytes
• antibodies

Article highlights

• NKG2D is a potent activating receptor expressed on virtually all cytotoxic lymphocytes including Natural Killer (NK) cells, CD8 #x3B1;β T cells and γδ T cells. NKG2D engagement by its ligands (i.e. NKG2DL) stimulates both cytotoxicity and cytokine secretion of such cytotoxic lymphocytes.

• NKG2DL are cell stress-inducible MHC class-I related glycoproteins. They are usually absent from the surface of healthy cells, but rather mark infected or transformed cells for elimination by cytotoxic lymphocytes and can thus be considered as immunological “kill me” signals.

• Tumor cells escape from NKG2D-mediated immunosurveillance by release of NKG2DL in soluble forms. This process not only reduces NKG2DL surface density on tumor cells, but may also locally and systemically impair the functions of NKG2D-expressing cytotoxic lymphocytes.

• NKG2D-CAR engineered T cells or NK cells are currently tested in clinical trials for the treatment of hematologic malignancies and solid cancers with encouraging preliminary data. In addition, preclinical studies also revealed the potential of NKG2D-CAR engineered lymphocytes to target both, tumor cells and the immunosuppressive tumor microenvironment.

• Blocking NKG2DL shedding by tumor cells using NKG2DL-specific antibodies also constitutes a promising therapeutic approach awaiting clinical testing. Such therapeutic antibodies have the capacity to reinvigorate endogenous NKG2D-mediated immunosurveillance by enhancing tumor-associated NKG2DL expression.

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Declaration of interest

WS Wels is named as an inventor on patents and patent applications in the field of cancer immunotherapy owned by Georg-Speyer-Haus. A Steinle discloses financial interests in the subject matter due to scientific collaborations with Innate Pharma, Marseille, France, and PDI Therapeutics, La Jolla, USA. A Steinle also consults PDI Therapeutics and Cullinan MICA, and holds stock options of PDI Therapeutics. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This work was supported by institutional funds of the Institute for Molecular Medicine and the Georg-Speyer-Haus. The Georg-Speyer-Haus is funded jointly by the German Federal Ministry of Health and the Hessen State Ministry of Higher Education, Research and the Arts.