Cytotoxic markers and frequency predict functional capacity of natural killer cells infiltrating renal cell carcinoma.
OBJECTIVE
Renal cell carcinoma harbors high numbers of infiltrating lymphocytes with apparent limited efficacy in tumor control. This study focused on the natural killer (NK) cells infiltrating renal cell carcinoma.


METHODS
Tumor-infiltrating lymphocytes (TIL) were isolated from renal cell carcinoma and analyzed for NK cell frequency and phenotype (n = 34). NK cells were enriched and tested for effector function.


RESULTS
Two renal cell carcinoma subtypes were identified, one containing high (>20% of the lymphocyte population, n = 14), the other low (<20%, n = 20), NK cell numbers. NK cells of both groups were noncytolytic ex vivo but differed in CD16 and cytotoxic effector molecule expression as well as in their capacity to acquire cytotoxic activity: The majority of NK cells from tumors with high NK cell content (high NK-TIL) were CD16(bright), whereas few CD16bright NK cells were found in tumors with low NK cell frequencies (low NK-TIL). The CD16 dichotomy correlated with different capacities to develop cytotoxicity after short-term activation with interleukin-2 ex vivo: Low NK-TIL remained noncytolytic against K562 and unresponsive to signals via the activating receptor NKp46 despite expression of receptor and adaptor molecules. In contrast, high NK-TIL acquired cytotoxic function. As described for peripheral CD16bright NK cells, NK cells from high-NK tumors showed high per cell expression of granzyme A, granzyme B, and perforin. NK cells from low NK-TIL resembled CD16(neg/dim) peripheral NK cells with few cytotoxin+ cells and lower expression of perforin.


CONCLUSIONS
The extent of NK cell infiltration and the expression of markers (CD16 and cytotoxins) predict the functional capacity of NK cells infiltrating renal cell carcinoma and can be used to characterize subgroups of renal cell carcinoma.
Schleypen
Julia S
JS
Institute of Molecular Immunology, GSF National Research Center for Environment and Health, Munich, Germany.
Baur
Nicole
N
Kammerer
Robert
R
Nelson
Peter J
PJ
Rohrmann
Karl
K
Gröne
Elisabeth F
EF
Hohenfellner
Markus
M
Haferkamp
Axel
A
Pohla
Heike
H
Schendel
Dolores J
DJ
Falk
Christine S
CS
Noessner
Elfriede
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D002452:Cell Count; D002460:Cell Line; D003603:Cytotoxins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053804:Granzymes; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics
D003603:Cytotoxins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D017452:Receptors, IgG; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human