Leveraging NKG2D Ligands in Immuno-Oncology

Abstract

Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.

NKp44-based chimeric antigen receptor effectively redirects primary T cells against synovial sarcoma

“…The expression of cell surface ligands may be altered by various stimuli or stressors. For example, NKG2D ligands are upregulated by chemotherapy, radiation, and inflammation [ 26 , 27 ]. We investigated whether VPA, inflammatory cytokines (IFN-γ plus TNF-α), 5-AZA, GEM, and ionizing radiation (two gray) could induce the expression of NKp44 ligands.…”

“…The efficacy of CAR T-cell therapy also depends on the expression levels of ligands on the surface of tumor cells. NKG2D ligands are induced by various inflammatory stimuli or stresses [ 26 , 27 ]. The upregulation of ligands can enhance the effectiveness of CAR T cells.…”

Target tumor microenvironment by innate T cells

“…This intrinsic killing despite the absence of TCR engagement emerges due to high expression levels of NK activating receptors in iNKT cells for potent NK-mediated cytotoxicity ( Figures 2A, B ) ( 50 , 51 ). The capacity of iNKT cells to target TAMs through two distinct pathways provides an attractive method to reengineer the tumor microenvironment and stimulate endogenous CD8 cytotoxic T cells and NK cells ( 52 ). Another study reported that neuroblastoma TAMs were capable of cross-presenting neuroblastoma-derived endogenous glycosphingolipids from the TME, which could specifically activate iNKT cells and induce iNKT cell-mediated TAM killing ( 45 ).…”

The Immunotherapy and Immunosuppressive Signaling in Therapy-Resistant Prostate Cancer

“…NKG2D, an activating receptor expressed on the surface of NK cells and CD56+ and CD8+ T cells, plays a critical role in the innate immune system and is involved in the recognition and killing of virus-infected cells and tumor cells by NK cells [ 134 ]. NK cells are a preliminary factor for immune surveillance and tumor growth inhibition in the body’s immune system and can terminate tumor cells without antigen stimulation [ 135 ].…”