Nagarkatti M, Kaplan A M
J Immunol. 1985 Aug;135(2):1510-7.
The present investigation was initiated to determine the mechanism by which 1,3-bis(2-chloro-ethyl)-1-nitrosourea (BCNU) treatment of tumor-bearing mice results in a high percentage of surviving mice which are resistant to subsequent homologous tumor challenge. Spleen cells from C57BL/6 mice bearing the syngeneic LSA ascites tumor failed to demonstrate significant tumor-specific cytotoxic T lymphocyte (CTL) activity when stimulated in vitro with irradiated tumor cells. This lack of CTL activity correlated with the presence and high activity of two types of CTL-regulatory suppressor T cells (Ts), tumor-specific Thy-1+, Lyt-1-2+ and tumor-nonspecific Thy-1+, Lyt-1+2+ cells, as demonstrated by a double-positive selection technique. In contrast, spleen cells from BCNU-treated tumor-bearing mice generated high tumor-specific CTL activity when stimulated in vitro with irradiated tumor cells. This CTL activity correlated with the lack of demonstrable tumor-specific Ts and greatly diminished tumor-nonspecific Ts activity. The tumor-specific helper activity of Thy-1+, Lyt-1+,2- cells was found to be similar in both BCNU-treated and untreated tumor-bearing mice. BCNU-treated mice that survived a primary LSA tumor challenge (referred to as BCNU-cured mice) resisted subsequent challenge with the homologous (LSA) but not with a heterologous syngeneic tumor (EL-4). However, rejection of a secondary challenge with LSA tumor by BCNU-cured mice was inhibited by adoptive transfer of spleen cells from either normal mice or mice bearing LSA tumors. Furthermore, LSA tumor cells that failed to evoke tumor-specific CTL activity in normal mice could induce high CTL activity in BCNU-cured mice. The present study suggests that, in addition to its direct tumoricidal activity, BCNU inhibits the induction of tumor-specific Ts, thereby explaining why a high percentage of mice survive a primary syngeneic tumor challenge after treatment with BCNU, and also resist subsequent rechallenge with the homologous tumor.
开展本研究是为了确定用1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）处理荷瘤小鼠后，导致高比例存活小鼠对随后的同源肿瘤攻击产生抗性的机制。携带同基因LSA腹水瘤的C57BL/6小鼠的脾细胞，在用照射过的肿瘤细胞体外刺激时，未表现出显著的肿瘤特异性细胞毒性T淋巴细胞（CTL）活性。通过双阳性选择技术证明，这种CTL活性的缺乏与两种类型的CTL调节性抑制性T细胞（Ts），即肿瘤特异性Thy-1 +、Lyt-1 - 2 +和肿瘤非特异性Thy-1 +、Lyt-1 + 2 +细胞的存在和高活性相关。相反，用照射过的肿瘤细胞体外刺激时，来自BCNU处理的荷瘤小鼠的脾细胞产生了高肿瘤特异性CTL活性。这种CTL活性与未检测到的肿瘤特异性Ts的缺乏以及肿瘤非特异性Ts活性的大大降低相关。发现Thy-1 +、Lyt-1 +、2 -细胞的肿瘤特异性辅助活性在BCNU处理和未处理的荷瘤小鼠中相似。在原发性LSA肿瘤攻击中存活的BCNU处理小鼠（称为BCNU治愈小鼠）对随后的同源（LSA）肿瘤攻击有抗性，但对异源同基因肿瘤（EL-4）没有抗性。然而，正常小鼠或携带LSA肿瘤的小鼠的脾细胞的过继转移抑制了BCNU治愈小鼠对LSA肿瘤二次攻击的排斥反应。此外，在正常小鼠中未能引发肿瘤特异性CTL活性的LSA肿瘤细胞，可在BCNU治愈小鼠中诱导高CTL活性。本研究表明，除了其直接的杀肿瘤活性外，BCNU还抑制肿瘤特异性Ts的诱导，从而解释了为什么高比例的小鼠在用BCNU治疗后能在原发性同基因肿瘤攻击中存活，并且还能抵抗随后同源肿瘤的再次攻击。
