NKG2D and MICA/B shedding: a 'tag game' between NK cells and malignant cells
Samantha Xing1, Lucas Ferrari de Andrade1,2,3
1Precision Immunology Institute New York NY USA.
Abstract:
Natural killer (NK) cells are innate lymphocytes with cytotoxic functions and recognise target cells with the NK group 2D (NKG2D) receptor. Tumor cells are marked for NK-cell-mediated destruction upon expression of MICA and MICB (MICA/B), which are NKG2D ligands upregulated by many human cancers in response to cellular stress pathways associated with malignant transformation such as DNA damage and accumulation of misfolded proteins. However, MICA/B proteins are downregulated by tumor cells via intriguing molecular mechanisms, such as post-translational modifications in which the external domains of MICA/B are proteolytically cleaved by surface proteases and shed into the extracellular space. MICA/B shedding by cancer cells causes effective escape from NKG2D recognition and allows the development of cancers. Patients frequently have increased concentrations of soluble MICA/B molecules shed in the blood plasmas and sera, thus indicating that MICA/B shedding is a therapeutic target in immune-oncology. Here, we review the clinical significance of MICA/B shedding in cancer as well as novel immunotherapeutic approaches that aim to restore NKG2D-mediated surveillance. We also briefly discuss potential roles of MICA/B shedding beyond oncology, such as in viral infections and immune tolerance. This review will help to inform the future developments of NKG2D-based immunotherapies.
Insights
Cancer cells evade immune detection by shedding MICA/B proteins, which are ligands for the NKG2D receptor on natural killer (NK) cells. Targeting this MICA/B shedding offers a promising avenue for cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Natural killer (NK) cells are crucial innate immune cells that eliminate target cells via receptors like NKG2D.
- Tumor cells express NKG2D ligands, MICA/B, which mark them for NK cell destruction.
- Cancer cells exploit MICA/B shedding to evade NK cell surveillance.
Purpose of the Study:
- To review the clinical significance of MICA/B shedding in cancer.
- To explore novel immunotherapeutic strategies targeting MICA/B shedding.
- To discuss the broader implications of MICA/B shedding in disease.
Main Methods:
- Literature review of MICA/B shedding mechanisms and clinical relevance.
- Analysis of MICA/B shedding as a therapeutic target in immune-oncology.
- Exploration of NKG2D-based immunotherapies.
Main Results:
- MICA/B shedding is a key mechanism for tumor immune escape.
- Elevated soluble MICA/B levels in patients indicate its clinical significance.
- MICA/B shedding is a viable therapeutic target for restoring anti-cancer immunity.
Conclusions:
- Restoring NKG2D-mediated surveillance by inhibiting MICA/B shedding is a promising cancer immunotherapy strategy.
- Understanding MICA/B shedding is vital for developing effective immunotherapies.
- MICA/B shedding may also play roles in viral infections and immune tolerance.
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