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A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
NK cells use NKG2D to recognize a mouse renal cancer (Renca), yet require intercellular adhesion molecule-1
Karen Abdool1, Erika Cretney, Alan D Brooks
1Laboratory of Experimental Immunology, National Cancer Institute-Frederick, Building 560, Frederick, MD 21702, USA.
Abstract:
The NKG2D receptor on NK cells can recognize a variety of ligands on the tumor cell surface. Using a mouse renal cancer (Renca), we show that NKG2D recognition by NK cells was crucial for their ability to limit tumor metastases in vivo in both liver and lungs using perforin-dependent effector mechanisms. However, for the R331 cell line established from Renca, NKG2D recognition and perforin-dependent lysis played no role in controlling liver metastases. R331 cells were also more resistant to perforin-dependent lysis by NK cells in vitro. We therefore used these phenotypic differences between Renca and R331 to further investigate the crucial receptor:ligand interactions required for triggering lytic effector functions of NK cells. Reconstitution of R331 cells with ICAM-1, but not Rae-1gamma, restored NKG2D-mediated, perforin-dependent lysis. Interestingly, R331 cells were efficiently lysed by NK cells using death ligand-mediated apoptosis. This death ligand-mediated killing did not depend on NKG2D recognition of its ligands on tumor cells. This result suggests that the intracellular signaling in NK cells required for perforin and death ligand-mediated lysis of tumor target cell are quite distinct, and activation of both of these antitumor lytic effector functions of NK cells could improve therapeutic benefits for certain tumors.
Insights
Natural killer (NK) cells use NKG2D receptor recognition to limit renal cancer spread, but this pathway is ineffective against certain tumor variants. Alternative death ligand-mediated killing by NK cells offers a distinct therapeutic avenue.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Mechanisms
Background:
- Natural killer (NK) cells are crucial for innate immunity and tumor surveillance.
- The NKG2D receptor on NK cells recognizes stress-induced ligands on target cells, triggering cytotoxic responses.
- Understanding NK cell activation pathways is vital for developing effective cancer immunotherapies.
Purpose of the Study:
- To investigate the role of NKG2D-mediated cytotoxicity in controlling renal cancer (Renca) metastasis.
- To elucidate the mechanisms by which Renca and its variant R331 cell lines are recognized and lysed by NK cells.
- To identify key receptor-ligand interactions essential for triggering NK cell lytic effector functions.
Main Methods:
- Utilized a mouse renal cancer (Renca) model to study tumor metastasis in vivo.
- Compared the susceptibility of Renca and R331 cell lines to NK cell-mediated lysis in vitro and in vivo.
- Investigated the role of NKG2D receptor-ligand interactions (ICAM-1, Rae-1gamma) and death ligand pathways in NK cell cytotoxicity.
Main Results:
- NKG2D recognition and perforin-dependent lysis by NK cells were critical for limiting Renca metastases in liver and lungs.
- NKG2D recognition and perforin-dependent lysis were ineffective against the R331 cell line, which showed resistance to this killing mechanism.
- Reconstitution of R331 cells with ICAM-1, but not Rae-1gamma, restored NKG2D-mediated lysis.
- R331 cells were efficiently lysed by NK cells via death ligand-mediated apoptosis, a pathway independent of NKG2D recognition.
Conclusions:
- NKG2D-mediated cytotoxicity is crucial for controlling certain renal cancer metastases through perforin-dependent mechanisms.
- Tumor cell resistance to NKG2D-mediated lysis can be overcome by ICAM-1 expression, restoring NK cell killing.
- Distinct intracellular signaling pathways govern perforin and death ligand-mediated NK cell lysis, suggesting dual activation strategies for enhanced cancer therapy.
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