Modulation of tumor-infiltrating lymphocytes derived from human renal cell carcinoma by interleukin-4.

C L Tso, T Duckett, J B deKernion, A S Belldegrun
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引用次数: 6

Abstract

Current methods of expanding tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma bulk cultures result in a heterogeneous population of cells with low tumor-killing specificity. To improve the yield of cells with higher autologous and lower nonspecific cytotoxicity, interleukin-4 (IL-4) was added to high (1,000 U/ml)- and low (20 U/ml)-dose IL-2 and compared to cultures grown without IL-4 for proliferation, phenotype, and cytotoxicity against targets including autologous and allogeneic tumors. When compared to culture in IL-2 alone, the addition of IL-4 improved overall expansion in both high-dose (mean fold expansion of 2,061 vs. 1,087) and low-dose (mean fold expansion of 1,904 vs. 262) IL-2. Enhancement of TIL proliferation was dependent on the timing of IL-4 addition to the culture; augmented growth occurred only when IL-4 was added with or following activation by IL-2. The phenotype consisted primarily of CD3+/CD4+ lymphocytes with a reciprocal reduction in CD56+/CD16+ cells. Finally, there was a significant reduction in nonspecific cytotoxicity against K-562, M-14, and allogeneic tumor targets, but no significant change against autologous tumor. We conclude that IL-4 has an important regulatory effect on the expansion of renal cell carcinoma TILs in IL-2 by the promoting growth of CD3+/CD4+ lymphocytes and inhibiting the growth and nonspecific cytotoxicity associated with LAK-like CD16+/CD56+ cells. These findings may be beneficial in extracting more potent effector cells from bulk TIL culture for use in clinical trials.

白细胞介素-4对人肾细胞癌肿瘤浸润淋巴细胞的调节作用。
目前从肾细胞癌大量培养中扩增肿瘤浸润淋巴细胞(til)的方法导致细胞群异质性,肿瘤杀伤特异性低。为了提高具有较高自体和较低非特异性细胞毒性的细胞的产量,将白细胞介素-4 (IL-4)添加到高剂量(1,000 U/ml)和低剂量(20 U/ml)的IL-2中,并与不添加IL-4的培养物进行增殖、表型和细胞毒性的比较,以对抗包括自体和异体肿瘤在内的目标。与单独培养IL-2相比,IL-4的加入改善了高剂量IL-2(平均扩增2061倍对1087倍)和低剂量IL-2(平均扩增1904倍对262倍)的总体扩增。TIL增殖的增强取决于IL-4加入培养的时间;只有在IL-2激活的同时或之后加入IL-4时,生长才会增强。表型主要由CD3+/CD4+淋巴细胞组成,CD56+/CD16+细胞相互减少。最后,对K-562、M-14和异体肿瘤靶点的非特异性细胞毒性显著降低,但对自体肿瘤的非特异性细胞毒性无显著变化。我们得出结论,IL-4通过促进CD3+/CD4+淋巴细胞的生长,抑制与lak样CD16+/CD56+细胞相关的生长和非特异性细胞毒性,对IL-2中肾癌TILs的扩张具有重要的调节作用。这些发现可能有利于从散装TIL培养中提取更有效的效应细胞,用于临床试验。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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