Defective Infiltration of Natural Killer Cells in MICA/B-Positive Renal Cell Carcinoma Involves β2-Integrin-Mediated Interaction

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.

Melanoma Cells Inhibit NK Cell Functions—Letter

“…These results provide potential mechanistic insights for a number of observations previously made by others and by ourselves (2)(3)(4)(5). Indeed, we found that NK cell infiltration is poor, if at all detectable, in various types of human cancers.…”

“…Further studies using autologous cancer cells are warranted to clarify whether molecular mechanisms underlying impaired NK cell functions in a tumor setting are specifically related to neoplastic transformation (3). Nevertheless, the data by Pietra and colleagues, Mamessier and colleagues, and Erdag and colleagues (1, 2, 4, 7), together with our observations question A B Figure 1.…”

“…We also found that 310 (92%) of 336 hepatocellular carcinomas (HCC), 376 (97%) of 385 breast cancers (Sconocchia and colleagues, unpublished data), and 108 (92%) of 117 renal cell carcinomas (RCC; ref. 3) showed no evidence of CD56þ cell infiltration.…”

An overview of renal cell cancer: Pathology and genetics

“…Sarcomatoid changes can also occur in clear cell renal carcinoma and is associated with poor prognosis [5,9]. Most renal cell carcinomas have little inflammatory response, but sometimes an intense lymphocytic or neutrophilic infiltrate with natural killer cells is present [10] and there is an association between a strong lymphocytic infiltration and worse outcome [11]. Clear cell renal cell carcinomas most commonly metastasize hematogeneously via the vena cava primarily to the lung.…”

Regulation Roles of MICA and NKG2D in Human Renal Cancer Cells

“…Renal cell carcinoma is the most common type of kidney cancer and follows an unpredictable disease course (Noon et al, 2010), represents approximately 2% -3% in all malignant tumor, a median survival of approximately 1 yearb (Cohen et al, 2005;Sconocchia et al, 2009). Annual incidence increased at about 2%, nearly 100, 000 cases of patients died of kidney cancer each year.…”