Tuttle T M, Inge T H, Lind D S, Bear H D
Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Surg Oncol. 1992 Aug;1(4):299-307. doi: 10.1016/0960-7404(92)90091-x.
Treatment of human cancer with tumour-specific T lymphocytes is limited by the frequent unavailability of autologous tumour to stimulate T-cell growth and by the toxicity associated with high-dose interleukin-2 (IL-2) treatment. In the present study we demonstrate that Bryostatin 1 (B) plus ionomycin (I) can substitute for tumour antigen and activate tumour-bearing hosts' T-cells which provide long-term protection against tumour challenge after adoptive transfer. Lymphocytes obtained from the popliteal lymph nodes (DLN) draining an MCA-105 footpad sarcoma were stimulated with B/I, and then cultured for 7 days with 20 U ml-1 IL-2. This in vitro stimulation protocol consistently expanded cell numbers greater than 20-fold during 7 days. Mice given B/I-stimulated draining lymph node (DLN) cells were protected from specific i.v. tumour challenge for at least 15 weeks after adoptive transfer, even in the absence of IL-2 treatment. Tumour immunity conferred by B/I-activated DLN cells was systemic and independent of host T-cells. However, resistance to tumour challenge was lost when either CD4+ or CD8+ T-cells were depleted in vivo. These studies indicate that DLN cells activated with bryostatin 1 and ionomycin persist long-term in vivo as functional memory cells after adoptive transfer.
用肿瘤特异性T淋巴细胞治疗人类癌症受到以下因素的限制：自体肿瘤常常无法用于刺激T细胞生长，以及与高剂量白细胞介素-2（IL-2）治疗相关的毒性。在本研究中，我们证明了苔藓抑素1（B）加离子霉素（I）可以替代肿瘤抗原并激活荷瘤宿主的T细胞，这些T细胞在过继转移后能提供针对肿瘤攻击的长期保护。从引流MCA-105足垫肉瘤的腘窝淋巴结（DLN）获得的淋巴细胞用B/I刺激，然后用20 U/ml IL-2培养7天。这种体外刺激方案在7天内持续使细胞数量扩增超过20倍。接受B/I刺激的引流淋巴结（DLN）细胞的小鼠在过继转移后至少15周内受到保护，免受特异性静脉内肿瘤攻击，即使在没有IL-2治疗的情况下也是如此。B/I激活的DLN细胞赋予的肿瘤免疫是全身性的，且不依赖于宿主T细胞。然而，当体内CD4 +或CD8 + T细胞被清除时，对肿瘤攻击的抵抗力就会丧失。这些研究表明，用苔藓抑素1和离子霉素激活的DLN细胞在过继转移后作为功能性记忆细胞在体内长期持续存在。
