Lefor A T, Fabian D F
Department of Surgery, Kern Medical Center, Bakersfield, California 93305, USA.
J Surg Res. 1998 Feb 15;75(1):49-53. doi: 10.1006/jsre.1997.5242.
Tumors transfected with intercellular adhesion molecule-1 (ICAM-1), a known activator of resting T-cells, show an increased response to adoptive immunotherapy in vivo. This salutary effect may be due to increased sensitivity of the transfected tumor cells to cell-mediated cytotoxicity or an increased activity of the effector cells in the presence of increased amounts of ICAM-1.
MCA105 fibrosarcoma cells were transfected with the gene for ICAM-1, and a clone (Cl149) demonstrating significantly increased expression of ICAM-1 by fluorescent-activated cell sorter (FACS) and enzyme-linked immunosorbent assay (ELISA) compared to parental tumor was selected and cultured. Tumor infiltrating lymphocytes (TILs) were cultured in vitro from MCA105 and Cl149 tumors. K562 tumor cells were used as controls.
TILs derived from MCA105 tumors lysed MCA105 (32% at 40:1) and Cl149 (52% at 40:1) target cells but not K562 (3%) demonstrating TIL specificity. TILs derived from Cl149 showed increased lysis of both target cells tested: MCA105 (62% at 40:1, P < 0.05) and Cl149 (98%) compared to lysis of the same target cells by MCA105 TILs as well as being specific (K562, 1%).
These studies demonstrate that increased expression of ICAM-1 by a tumor cell results in increased lysis by TILs derived from either a tumor with enhanced ICAM-1 expression or a parental tumor, compared to the lysis of parental tumor target cells. In addition, TILs derived from a tumor with enhanced expression of ICAM-1 have significantly increased antitumor efficacy compared to TILs from the parental tumor, suggesting a possible mechanism for previously observed in vivo antitumor effects. These results suggest a new strategy for improving the efficacy of adoptive immunotherapy, by using lymphocytes derived from genetically altered tumors. The study of lymphocytes from genetically modified tumor cells may enable the elucidation of properties of various molecules believed important in cellular cytotoxicity.
用细胞间黏附分子-1（ICAM-1，一种已知的静止T细胞激活剂）转染的肿瘤在体内对过继性免疫疗法表现出增强的反应。这种有益效果可能是由于转染的肿瘤细胞对细胞介导的细胞毒性敏感性增加，或者是在ICAM-1量增加的情况下效应细胞活性增强。
用ICAM-1基因转染MCA105纤维肉瘤细胞，通过荧光激活细胞分选仪（FACS）和酶联免疫吸附测定（ELISA）筛选出与亲代肿瘤相比ICAM-1表达显著增加的克隆（Cl149）并进行培养。从MCA105和Cl149肿瘤中体外培养肿瘤浸润淋巴细胞（TILs）。K562肿瘤细胞用作对照。
源自MCA105肿瘤的TILs可裂解MCA105（40:1时为32%）和Cl149（40:1时为52%）靶细胞，但不能裂解K562（3%），表明TILs具有特异性。与MCA105 TILs对相同靶细胞的裂解相比，源自Cl149的TILs对两种测试靶细胞的裂解均增加：MCA105（40:1时为62%，P<0.05）和Cl149（98%），并且也具有特异性（K562，为1%）。
这些研究表明，与亲代肿瘤靶细胞的裂解相比，肿瘤细胞ICAM-1表达增加导致源自ICAM-1表达增强的肿瘤或亲代肿瘤的TILs的裂解增加。此外，与源自亲代肿瘤的TILs相比，源自ICAM-1表达增强的肿瘤的TILs具有显著增强的抗肿瘤功效，提示了先前观察到的体内抗肿瘤效应的一种可能机制。这些结果提示了一种通过使用源自基因改造肿瘤的淋巴细胞来提高过继性免疫疗法疗效的新策略。对来自基因修饰肿瘤细胞的淋巴细胞的研究可能有助于阐明各种被认为在细胞毒性中重要的分子的特性。
