Peppoloni S, Mathieson B J, Herberman R B, Overton R W, Gorelik E
Cancer Immunol Immunother. 1987;24(1):49-56. doi: 10.1007/BF00199832.
We have analyzed the effects of high doses of cyclophosphamide (Cy) on primary and secondary antitumor immune response against immunogenic (tum-) variants of Lewis lung carcinoma (3LL) treated in vitro with UV light. Normal mice and mice previously immunized with tum- clones wer inoculated i.p. with Cy (200 mg/kg body weight) and 24 h later challenged intrafootpad with tum- or parental 3LL cells. Cy treatment suppressed the primary immune response of normal animals and allowed the growth of tum- cells. In contrast, Cy-treated immune mice rejected the tumor challenge. The in vivo treatment with Cy decreased the total number of lymphoid cells in the spleens, as well as the proportion of B lymphocytes; however, it increased the percentage of both Lyt2+ and L3T4+ lymphocytes. Thus, the immunosuppressive effects of Cy on the primary antitumor response could not be attributed to elimination of major T lymphocyte subpopulations. Although the treatment of immune mice with Cy did not significantly impair their antitumor resistance, nor the proportion of Lyt2+ and L3T4+ lymphocytes in their spleens, the in vitro generation of cytotoxic T lymphocytes (CTL) was markedly reduced. After Cy treatment, the proliferative ability of spleen cells in response to interleukin-2 (IL-2) was substantially impaired. Using monoclonal antibodies to the IL-2 receptor, we found that Cy-treated T lymphocytes failed to fully express the IL-2 receptor following in vitro stimulation with irradiated tumor cells. In line with these findings, the in vitro generation of CTL was not restored by addition of recombinant IL-2 to the cultures. In vivo experiments using purified functional subsets of immune T cells showed that Lyt1+, but not Lyt2+ lymphocytes were able to transfer antitumor immunity in normal irradiated recipients. Therefore, since Ly1+ T lymphocytes were responsible for the antitumor resistance in vivo, the Cy-induced impairment of CTL generation did not affect the ability of immune mice to reject a secondary tumor challenge.
我们分析了高剂量环磷酰胺（Cy）对经紫外线体外处理的Lewis肺癌（3LL）免疫原性（肿瘤 - ）变体的原发性和继发性抗肿瘤免疫反应的影响。正常小鼠和先前用肿瘤克隆免疫的小鼠经腹腔注射Cy（200mg/kg体重），24小时后用肿瘤或亲本3LL细胞进行足垫内攻击。Cy处理抑制了正常动物的原发性免疫反应，并使肿瘤细胞生长。相反，经Cy处理的免疫小鼠排斥肿瘤攻击。体内用Cy处理可减少脾脏中淋巴细胞的总数以及B淋巴细胞的比例；然而，它增加了Lyt2 +和L3T4 +淋巴细胞的百分比。因此，Cy对原发性抗肿瘤反应的免疫抑制作用不能归因于主要T淋巴细胞亚群的消除。虽然用Cy处理免疫小鼠并没有显著损害它们的抗肿瘤抵抗力，也没有损害它们脾脏中Lyt2 +和L3T4 +淋巴细胞的比例，但细胞毒性T淋巴细胞（CTL）的体外生成明显减少。Cy处理后，脾细胞对白介素 - 2（IL - 2）的增殖能力受到严重损害。使用针对IL - 2受体的单克隆抗体，我们发现经Cy处理的T淋巴细胞在受到照射的肿瘤细胞体外刺激后未能完全表达IL - 2受体。与这些发现一致，向培养物中添加重组IL - 2并不能恢复CTL的体外生成。使用免疫T细胞纯化功能亚群的体内实验表明，Lyt1 +而非Lyt2 +淋巴细胞能够在正常受照射的受体中传递抗肿瘤免疫力。因此，由于Ly1 + T淋巴细胞在体内负责抗肿瘤抵抗力，Cy诱导的CTL生成受损并不影响免疫小鼠排斥继发性肿瘤攻击的能力。
