PURPOSE: 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. EXPERIMENTAL DESIGN: 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. CONCLUSION: 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.
PURPOSE: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. EXPERIMENTAL DESIGN: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. CONCLUSION: 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: Shona Hendry; Roberto Salgado; Thomas Gevaert; Prudence A Russell; Tom John; Bibhusal Thapa; Michael Christie; Koen van de Vijver; M V Estrada; Paula I Gonzalez-Ericsson; Melinda Sanders; Benjamin Solomon; Cinzia Solinas; Gert G G M Van den Eynden; Yves Allory; Matthias Preusser; Johannes Hainfellner; Giancarlo Pruneri; Andrea Vingiani; Sandra Demaria; Fraser Symmans; Paolo Nuciforo; Laura Comerma; E A Thompson; Sunil Lakhani; Seong-Rim Kim; Stuart Schnitt; Cecile Colpaert; Christos Sotiriou; Stefan J Scherer; Michail Ignatiadis; Sunil Badve; Robert H Pierce; Giuseppe Viale; Nicolas Sirtaine; Frederique Penault-Llorca; Tomohagu Sugie; Susan Fineberg; Soonmyung Paik; Ashok Srinivasan; Andrea Richardson; Yihong Wang; Ewa Chmielik; Jane Brock; Douglas B Johnson; Justin Balko; Stephan Wienert; Veerle Bossuyt; Stefan Michiels; Nils Ternes; Nicole Burchardi; Stephen J Luen; Peter Savas; Frederick Klauschen; Peter H Watson; Brad H Nelson; Carmen Criscitiello; Sandra O'Toole; Denis Larsimont; Roland de Wind; Giuseppe Curigliano; Fabrice André; Magali Lacroix-Triki; Mark van de Vijver; Federico Rojo; Giuseppe Floris; Shahinaz Bedri; Joseph Sparano; David Rimm; Torsten Nielsen; Zuzana Kos; Stephen Hewitt; Baljit Singh; Gelareh Farshid; Sibylle Loibl; Kimberly H Allison; Nadine Tung; Sylvia Adams; Karen Willard-Gallo; Hugo M Horlings; Leena Gandhi; Andre Moreira; Fred Hirsch; Maria V Dieci; Maria Urbanowicz; Iva Brcic; Konstanty Korski; Fabien Gaire; Hartmut Koeppen; Amy Lo; Jennifer Giltnane; Marlon C Rebelatto; Keith E Steele; Jiping Zha; Kenneth Emancipator; Jonathan W Juco; Carsten Denkert; Jorge Reis-Filho; Sherene Loi; Stephen B Fox Journal: Adv Anat Pathol Date: 2017-11 Impact factor: 3.875