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Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Defective infiltration of natural killer cells in MICA/B-positive renal cell carcinoma involves
Giuseppe Sconocchia1, Giulio Cesare Spagnoli, Domenico Del Principe
1CNR, Institute for Organ Transplantation and Immunocytology, Rome, Italy. giuseppe.sconocchia@cnr.it
Abstract:
We have explored MICA/B expression and its relationship with innate inflammatory infiltrate in renal cell carcinoma (RCC). The expression of MICA/B, CD16, CD56, and CD68 in 140 RCC lesions contained in a tissue microarray (TMA) was investigated by immunohistochemistry. MICA/B gene and protein expressions in Caki-1 cells were analyzed by reverse transcription-polymerase chain reaction and flow cytometry, respectively. Natural killer (NK) cells were studied by flow cytometry. All the RCC lesions (n = 140) were MICA/B-positive. MICA/B was mainly expressed in the cytoplasm of tumor cells, whereas stromal cells were negative. Renal cell carcinoma lesions showed low NK cell infiltration, although they were rich in CD16(+)CD56(-) cells, strongly resembling macrophages. CD16(+) macrophage infiltration was more frequently detectable in metastatic lesions compared with primary tumors (P = .0223) and was associated with poor RCC differentiation (P = .007). To investigate mechanisms potentially underlying the lack of NK cells infiltration into MICA/B-positive RCC lesions, we used Caki-1 RCC cells. Caki-1 expressed MICA and MICB genes. However, MICA protein was not detectable in Caki-1 cells, whereas MICB protein was detectable in their cytoplasm and on the cell membrane. Coculture of peripheral blood mononuclear cells with Caki-1, K562, HCT116, respectively, resulted in CD56(+)CD16(+) NK cells deletion without affecting CD56(+)/CD16(-) NK subset and immature NK cells generated in vitro from CD34(+) cells. Natural killer cell apoptosis seemed to be preferentially triggered by cancer cells because HLA-A0201(+) NK cells were only marginally affected by allogeneic HLA-A0201(-) peripheral blood mononuclear cells. Caki-1 cell-mediated NK cell apoptosis was reduced by an anti-beta(2)-integrin (CD18) monoclonal antibody but was NKG2D-, granule exocytosis-, and caspase-independent.
Insights
Renal cell carcinoma (RCC) lesions express MICA/B, but show low natural killer (NK) cell infiltration. Cancer cells induce NK cell apoptosis, suggesting a mechanism for immune evasion in MICA/B-positive RCC.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- MICA/B expression is implicated in immune responses.
- Renal cell carcinoma (RCC) is a complex malignancy with varied immune infiltration.
- Natural killer (NK) cells play a crucial role in anti-tumor immunity.
Purpose of the Study:
- To investigate MICA/B expression in RCC.
- To analyze the relationship between MICA/B and innate inflammatory infiltrate in RCC.
- To explore the mechanisms of NK cell interaction with RCC cells.
Main Methods:
- Immunohistochemistry on 140 RCC tissue microarrays (TMAs).
- Reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry for gene and protein expression.
- Coculture assays of peripheral blood mononuclear cells (PBMCs) with RCC cell lines.
Main Results:
- All RCC lesions (n=140) were MICA/B-positive, primarily in tumor cell cytoplasm.
- RCC lesions exhibited low NK cell infiltration but high CD16(+)CD56(-) cells resembling macrophages.
- RCC cells induced apoptosis in CD56(+)CD16(+) NK cells, mediated partly by anti-beta(2)-integrin (CD18) and independent of NKG2D.
Conclusions:
- MICA/B expression is a feature of RCC.
- RCC lesions recruit macrophage-like cells and evade NK cell infiltration.
- RCC cells actively induce NK cell apoptosis, contributing to immune evasion.
