Gunji Y, Lewis J, Gorelik E
Department of Pathology, Pittsburgh Cancer Institute, University of Pittsburgh, PA.
Blood Coagul Fibrinolysis. 1990 Dec;1(6):663-72.
The biological significance of the interaction of the haemostatic factors with tumour cells remains unclear. It has been hypothesized that fibrin deposition around tumour cells could help those cells to escape destruction by cytotoxic effector cells. To obtain direct evidence in support of this possibility, the effect of fibrin formation on in vitro cytotoxicity of human natural killer (NK) or lymphokine-activated killer (LAK) cells was investigated by comparing their cytotoxic activity with various human tumour cell lines in the presence of human serum or plasma. The data demonstrate that pre-incubation of human tumour cells with plasma, but not serum, substantially diminished or completely abrogated the cytotoxic effects of these killer cells. This was shown to be due to fibrin formation. The degree of coagulation and the number of radioactive tumour cells trapped in the clot correlated with the extent of inhibition of NK or LAK cytotoxicity. Abrogation of LAK activity was also observed when the effector cells were pre-exposed to plasma or when effector and target cells were simultaneously mixed with plasma and trapped in a fibrin clot. Similar results were obtained when, instead of whole plasma, the cytotoxic effect of LAK and NK cells was studied in the presence of fibrinogen and thrombin. When heparin was added, fibrin formation was prevented and no inhibition of LAK/NK cell cytotoxicity was observed. In studies of the mechanisms of inhibition of LAK cell activity by fibrin, target - effector cell conjugate formation was found to be blocked. When plasma was added post-binding (15-30 min after mixing effector and target cells) although coagulation occurred, no effect on cytotoxicity was observed, supporting the conclusion that fibrin interfered with binding rather than the lytic phase of cytotoxic cell activity. Thus, the present data demonstrate that fibrin deposition around tumour and/or effector cells can protect tumour cells from immune destruction and diminish the efficiency of the cytotoxic LAK/NK cells.
止血因子与肿瘤细胞相互作用的生物学意义仍不清楚。据推测，肿瘤细胞周围的纤维蛋白沉积可能有助于这些细胞逃避细胞毒性效应细胞的破坏。为了获得支持这种可能性的直接证据，通过比较在人血清或血浆存在下它们对各种人类肿瘤细胞系的细胞毒性活性，研究了纤维蛋白形成对人自然杀伤（NK）细胞或淋巴因子激活的杀伤（LAK）细胞体外细胞毒性的影响。数据表明，人肿瘤细胞与血浆而非血清预孵育，会显著降低或完全消除这些杀伤细胞的细胞毒性作用。结果表明这是由于纤维蛋白形成所致。凝血程度以及凝块中捕获的放射性肿瘤细胞数量与NK或LAK细胞毒性的抑制程度相关。当效应细胞预先暴露于血浆中或效应细胞与靶细胞同时与血浆混合并被困在纤维蛋白凝块中时，也观察到LAK活性的消除。当用纤维蛋白原和凝血酶代替全血浆研究LAK和NK细胞的细胞毒性作用时，得到了类似的结果。加入肝素后，可防止纤维蛋白形成，未观察到LAK/NK细胞毒性的抑制。在研究纤维蛋白抑制LAK细胞活性的机制时，发现靶细胞与效应细胞结合物的形成受到阻碍。当在结合后（效应细胞与靶细胞混合后15 - 30分钟）加入血浆时，尽管发生了凝血，但未观察到对细胞毒性的影响，这支持了纤维蛋白干扰结合而非细胞毒性细胞活性的裂解阶段这一结论。因此，目前的数据表明，肿瘤和/或效应细胞周围的纤维蛋白沉积可保护肿瘤细胞免受免疫破坏，并降低细胞毒性LAK/NK细胞的效率。
