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Characteristics of tumor infiltration by adoptively transferred and endogenous natural‐killer cells in a syngeneic rat model: Implications for the mechanism behind anti‐tumor responses
Author(s) -
Hagenaars M.,
Zwaveling S.,
Kuppen P. J. K.,
Ensink N. G.,
Eggermont A. M. M.,
Hokland M. E.,
Basse P. H.,
van de Velde C. J. H.,
Fleuren G. J.,
Nannmark U.
Publication year - 1998
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19981209)78:6<783::aid-ijc17>3.0.co;2-c
Subject(s) - tumor microenvironment , lymphokine activated killer cell , interleukin 12 , natural killer cell , biology , adoptive cell transfer , nk 92 , cancer research , extracellular matrix , infiltration (hvac) , pathology , immune system , stroma , interleukin 21 , chemistry , cytotoxic t cell , immunology , microbiology and biotechnology , t cell , immunohistochemistry , medicine , in vitro , biochemistry , physics , thermodynamics
Interleukin‐2‐activated, cultured NK cells (A‐NK) cells were adoptively transferred into a syngeneic rat liver‐tumor model. The kinetics of tumor infiltration by NK cells, originating either from adoptively transferred or from endogenous sources, the localization of these cells in the tumor, and their interactions with extracellular‐matrix proteins were studied by immunohistochemistry and transmission‐electron microscopy. The adoptive transfer of A‐NK cells via the hepatic artery and s.c. injections of IL‐2 into rats bearing sub‐capsularly induced CC531 liver tumors, but also IL‐2 monotherapy, resulted in a significant increase of the number of NK cells both at the tumor border and in the tumor center. The majority of tumor‐infiltrating NK cells was present in the tumor stroma and only occasionally was an NK cell observed in a tumor nodule in direct contact with tumor cells. Observations by electron microscopy suggested that matrix proteins, abundantly present in the tumor stroma but absent in the tumor nodules, provide a substrate for migration of infiltrating cells, whereas tight structures of matrix proteins surrounding tumor nodules provide a barrier for establishment of direct NK‐cell‐to‐tumor‐cellcontact. Our results suggest that direct NK‐cell‐to‐target‐cell‐contact‐mediated lysis is of minor importance for attaining an anti‐tumor effect in this model. We hypothesize that treatment of tumor‐bearing rats with A‐NK cells and/or IL‐2 initiates a cascade of events ( e.g., secretion of tumor‐killing cytokines and/or infiltration of other immune cells) ultimately leading to tumor regression. Int. J. Cancer 78:783–789, 1998. © 1998 Wiley‐Liss, Inc.