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Published on: February 21, 2021
NKG2D function protects the host from tumor initiation
Mark J Smyth1, Jeremy Swann, Erika Cretney
1Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. mark.smyth@petermac.org
Abstract:
The activation NKG2D receptor has been shown to play an important role in the control of experimental tumor growth and metastases expressing ligands for NKG2D; however, a function for this recognition pathway in host protection from de novo tumorigenesis has never been demonstrated. We show that neutralization of NKG2D enhances the sensitivity of wild-type (WT) C57BL/6 and BALB/c mice to methylcholanthrene (MCA)-induced fibrosarcoma. The importance of the NKG2D pathway was additionally illustrated in mice deficient for either IFN-gamma or tumor necrosis factor-related apoptosis-inducing ligand, whereas mice depleted of natural killer cells, T cells, or deficient for perforin did not display any detectable NKG2D phenotype. Furthermore, IL-12 therapy preventing MCA-induced sarcoma formation was also largely dependent on the NKG2D pathway. Although NKG2D ligand expression was variable or absent on sarcomas emerging in WT mice, sarcomas derived from perforin-deficient mice were Rae-1(+) and immunogenic when transferred into WT syngeneic mice. These findings suggest an important early role for the NKG2D in controlling and shaping tumor formation.
Insights
The NKG2D receptor is crucial for controlling new tumor formation. Blocking NKG2D increases susceptibility to methylcholanthrene-induced fibrosarcoma, highlighting its role in early cancer protection.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- The NKG2D receptor is known to control experimental tumor growth and metastasis.
- Its role in host protection against de novo tumorigenesis has not been previously demonstrated.
Purpose of the Study:
- To investigate the function of the NKG2D pathway in host protection against de novo tumor formation.
- To determine the role of NKG2D in methylcholanthrene (MCA)-induced fibrosarcoma development.
Main Methods:
- Neutralization of NKG2D in wild-type (WT) mice.
- Analysis of tumor development in mice deficient for IFN-gamma or TNF-related apoptosis-inducing ligand (TRAIL).
- Assessment of IL-12 therapy's efficacy in preventing sarcoma formation.
Main Results:
- Neutralizing NKG2D significantly enhanced susceptibility to MCA-induced fibrosarcoma in WT mice.
- The NKG2D pathway was critical for protection mediated by IFN-gamma and TRAIL.
- IL-12 therapy's anti-sarcoma effects were largely dependent on the NKG2D pathway.
- Sarcomas from perforin-deficient mice showed NKG2D ligand expression (Rae-1) and were immunogenic in WT mice.
Conclusions:
- The NKG2D pathway plays a significant role in early control and shaping of tumor formation.
- NKG2D is essential for host defense against de novo tumorigenesis.
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