Agrawal S, Marquet J, Delfau-Larue M H, Copie-Bergman C, Jouault H, Reyes F, Bensussan A, Farcet J P
Department of Immunology, and INSERM Research Units, France.
J Clin Invest. 1998 Nov 1;102(9):1715-23. doi: 10.1172/JCI3784.
There is a dogma in tumor immunology that tumor-infiltrating lymphocytes (TIL) are defective based on their lack of antitumoral efficacy in vivo and on impaired response to in vitro functional tests. However, TIL have been compared usually with peripheral blood T lymphocytes, raising doubts on the conclusions drawn. Therefore, we compared TIL from B cell non-Hodgkin's lymphomas (NHL) with T cells from nonmalignant secondary lymphoid organs. NHL-TIL were unresponsive to activation by immobilized anti-CD3 mAb, although bypassing T cell receptor (TCR)/CD3 signaling led to proliferation. The poor proliferative responses of NHL-TIL could not be explained by quantitative defects in TCRzeta expression. NHL-TIL underwent marked spontaneous apoptosis in vitro with loss of approximately 50% of cells after 24 h of culture. This was associated with downregulation of the antiapoptotic Bcl-xL and Bcl-2 proteins, whereas viable NHL-TIL maintained their expression. IL-2, anti-CD3/IL-2, and manipulation of the Fas/Fas-ligand death pathway had no effect on NHL-TIL survival. Apoptosis was not due to increased cell cycling, as NHL-TIL were quiescent, nonproliferating cells. T cells from inflammatory, nonmalignant tissues gave similar functional results to NHL-TIL, suggesting the existence of factors common to the microenvironment of these diverse pathologies. Thus, the quiescent, anergic phenotype of NHL-TIL cannot be attributed solely to tumor factors, but rather is a feature of T cells from chronic inflammatory lesions.
肿瘤免疫学中有一个教条，即肿瘤浸润淋巴细胞（TIL）是有缺陷的，这基于它们在体内缺乏抗肿瘤功效以及对体外功能测试的反应受损。然而，TIL通常是与外周血T淋巴细胞进行比较，这使得由此得出的结论受到质疑。因此，我们将B细胞非霍奇金淋巴瘤（NHL）中的TIL与非恶性二级淋巴器官中的T细胞进行了比较。NHL-TIL对固定化抗CD3单克隆抗体的激活无反应，尽管绕过T细胞受体（TCR）/CD3信号传导会导致增殖。NHL-TIL增殖反应不佳无法用TCRζ表达的定量缺陷来解释。NHL-TIL在体外经历明显的自发凋亡，培养24小时后约50%的细胞丢失。这与抗凋亡蛋白Bcl-xL和Bcl-2的下调有关，而存活的NHL-TIL维持其表达。白细胞介素-2、抗CD3/白细胞介素-2以及Fas/Fas配体死亡途径的操纵对NHL-TIL的存活没有影响。凋亡并非由于细胞周期增加，因为NHL-TIL是静止的、不增殖的细胞。来自炎症性非恶性组织的T细胞给出了与NHL-TIL相似的功能结果，表明这些不同病理的微环境中存在共同因素。因此，NHL-TIL的静止、无反应表型不能仅仅归因于肿瘤因素，而是慢性炎症病变中T细胞的一个特征。
