Defective infiltration of natural killer cells in MICA/B-positive renal cell carcinoma involves beta(2)-integrin-mediated interaction.
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.
Sconocchia
Giuseppe
G
CNR, Institute for Organ Transplantation and Immunocytology, Rome, Italy. giuseppe.sconocchia@cnr.it
Spagnoli
Giulio Cesare
GC
Del Principe
Domenico
D
Ferrone
Soldano
S
Anselmi
Maurizio
M
Wongsena
Wachanan
W
Cervelli
Valerio
V
Schultz-Thater
Elke
E
Wyler
Stephen
S
Carafa
Vincenza
V
Moch
Holger
H
Terracciano
Luigi
L
Tornillo
Luigi
L
D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D018821:CD18 Antigens / Q000378:metabolism*; D019002:CD56 Antigen / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018821:CD18 Antigens; D019002:CD56 Antigen; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D017452:Receptors, IgG; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C428200:FCGR3B protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen