Lynch D H, Miller R E
Department of Immunobiology, Immunex Research and Development Corp., Seattle, Washington 98101.
J Exp Med. 1994 Jan 1;179(1):31-42. doi: 10.1084/jem.179.1.31.
A major obstacle to the effective use of adoptive immunotherapeutic treatment of cancer is the difficulty of obtaining tumor-reactive lymphocytes in either sufficient numbers or with appropriate in vivo function to make such an approach feasible. Previous studies have shown that antitumor cytotoxic T lymphocytes (CTL) with in vivo efficacy can be generated in vitro from lymphoid cells obtained from lymph nodes that drain the anatomical site of a tumor. Results presented here demonstrate that inclusion of interleukin 7 (IL-7) into the medium in which such CTL are cultured can support their growth in vitro for prolonged periods of time in the absence of repeated stimulation with either tumor stimulator cells or tumor antigen. More importantly, antitumor CTL propagated in medium containing IL-7 have retained both their antigenic specificity and their ability to reject tumors in vivo subsequent to intravenous injection. Parallel cultures of antitumor CTL similarly cultured in medium containing only IL-2 could only be maintained for 5-6 wk, after which the number and proportion of viable cells that were recoverable from such cultures progressively decreased. Phenotypic analysis of CTL maintained after extended culture (i.e., 22 mo) in medium containing IL-7 demonstrated them to be CD3+4-8+ T cells. These cells were also found to express lymphocyte function associated 1, intercellular adhesion molecule 1, and Mel-14 cell interaction molecules. The data also demonstrate that these CTL do not require the presence of antigen-presenting cell populations to mount a proliferative response to tumor stimulator cells. Cells in these cultures were also demonstrated to produce IL-2 after stimulation with irradiated tumor cells, thereby indicating that these CTL have become independent of the requirement for CD4+ helper cells to survive and function either in vitro or in vivo. Collectively, the findings that IL-7 can beneficially augment the generation, and propagate the long-term growth, of antitumor CTL from lymph nodes draining a tumor site may have profound implications for promoting the immunotherapeutic treatment of cancer in humans.
有效利用过继性免疫疗法治疗癌症的一个主要障碍是难以获得足够数量或具有适当体内功能的肿瘤反应性淋巴细胞，以使这种方法可行。先前的研究表明，具有体内疗效的抗肿瘤细胞毒性T淋巴细胞（CTL）可在体外从引流肿瘤解剖部位的淋巴结获得的淋巴细胞中产生。此处呈现的结果表明，将白细胞介素7（IL-7）添加到培养此类CTL的培养基中，可在无肿瘤刺激细胞或肿瘤抗原反复刺激的情况下，在体外长时间支持其生长。更重要的是，在含有IL-7的培养基中增殖的抗肿瘤CTL在静脉注射后仍保留其抗原特异性和体内排斥肿瘤的能力。在仅含有IL-2的培养基中类似培养的抗肿瘤CTL平行培养物只能维持5 - 6周，此后从这些培养物中可回收的活细胞数量和比例逐渐下降。对在含有IL-7的培养基中延长培养（即22个月）后维持的CTL进行表型分析，结果表明它们是CD3 + 4 - 8 + T细胞。还发现这些细胞表达淋巴细胞功能相关抗原1、细胞间黏附分子1和Mel-14细胞相互作用分子。数据还表明，这些CTL对肿瘤刺激细胞产生增殖反应时不需要抗原呈递细胞群体的存在。这些培养物中的细胞在受到照射的肿瘤细胞刺激后也被证明会产生IL-2，从而表明这些CTL在体外或体内生存和发挥功能时已不再依赖CD4 +辅助细胞。总体而言，IL-7可有益地增强从引流肿瘤部位的淋巴结产生抗肿瘤CTL并促进其长期生长的这一发现，可能对推动人类癌症的免疫治疗具有深远意义。
