title: Cytotoxic markers and frequency predict functional capacity of natural killer cells infiltrating renal cell carcinoma.
abstract: 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.
authors.affiliation: Institute of Molecular Immunology, GSF National Research Center for Environment and Health, Munich, Germany.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Schleypen
authors.forename: Nicole
authors.initials: N
authors.lastname: Baur
authors.forename: Robert
authors.initials: R
authors.lastname: Kammerer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
authors.forename: Karl
authors.initials: K
authors.lastname: Rohrmann
authors.forename: Elisabeth F
authors.initials: EF
authors.lastname: Gröne
authors.forename: Markus
authors.initials: M
authors.lastname: Hohenfellner
authors.forename: Axel
authors.initials: A
authors.lastname: Haferkamp
authors.forename: Heike
authors.initials: H
authors.lastname: Pohla
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Schendel
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
authors.forename: Elfriede
authors.initials: E
authors.lastname: Noessner
mesh_terms: 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
chemical_list: 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