Transforming growth factor-beta-mediated down-regulation of antitumor cytotoxicity of spleen cells from MOPC-315 tumor-bearing mice engaged in tumor eradication following low-dose melphalan therapy.
Transforming growth factor-beta-mediated down-regulation of antitumor cytotoxicity of spleen cells from MOPC-315 tumor-bearing mice engaged in tumor eradication following low-dose melphalan therapy.
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转化生长因子-β 介导的 MOPC-315 荷瘤小鼠脾细胞抗肿瘤细胞毒性的下调，这些小鼠在低剂量美法仑治疗后进行肿瘤根除。
DOI：
10.1007/bf01533512
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Mokyr,MB
中科院分区：
文献类型：
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作者：
Weiskirch,LM;Bar-Dagan,Y;Mokyr,MB
我们之前已经证明，用低剂量的抗癌药物melphalan （l-苯丙氨酸芥；l-PAM）治疗携带大MOPC-315浆细胞瘤的小鼠，导致迄今免疫抑制的肿瘤携带者获得了CD8+T细胞介导的抗MOPC-315细胞毒性T淋巴细胞（CTL）活性，这种免疫有助于完全根除肿瘤。在这里提出的研究中，我们试图确定如何在低剂量化疗后获得这种抗肿瘤免疫，根据MOPC-315肿瘤细胞产生转化生长因子-β (TGF-β)的报道，这是一种免疫抑制细胞因子，可以下调CTL反应的产生。我们发现，低剂量pam治疗后CTL活性的获得并不是因为化疗导致MOPC-315肿瘤携带脾细胞对TGF-β介导的CTL生成抑制的敏感性降低。此外，即使是在7天前接受过- pam治疗并在体内获得CTL活性的MOPC-315荷瘤小鼠的脾脏细胞，在有或没有刺激肿瘤细胞的情况下，仅培养1天后，对TGF-β的抑制活性也很敏感。然而，由于低剂量化疗，MOPC-315肿瘤TGF-β的产生急剧下降。因此，低剂量pam治疗MOPC-315荷瘤小鼠的疗效可能至少部分归因于TGF-β产生的减少，TGF-β使肿瘤根除免疫的发展成为可能。
We have previously shown that treatment of mice bearing a large MOPC-315 plasmacytoma with a low dose of the anticancer drug melphalan (l-phenylalanine mustard;l-PAM) results in the acquisition of a potent CD8+T-cell-mediated anti-MOPC-315 cytotoxic T lymphocyte (CTL) activity by the hitherto immunosuppressed tumor bearers, and this immunity contributes to complete tumor eradication. In the studies presented here, we sought to determine how the acquisition of this antitumor immunity following low-dose chemotherapy is possible, in light of the report that MOPC-315 tumor cells produce transforming growth factor-β (TGF-β), an immunosuppressive cytokine that can down-regulate the generation of CTL responses. We found that the acquisition of CTL activity following low-dosel-PAM therapy is not due to a chemotherapy-induced decrease in the sensitivity of MOPC-315 tumor bearer spleen cells to TGF-β-mediated inhibition of CTL-generation. Moreover, even spleen cells from MOPC-315 tumor-bearing mice, which had receivedl-PAM therapy 7 days earlier and had acquired CTL activity in vivo, were sensitive to the inhibitory activity of TGF-β upon culture for as little as 1 day, with or without stimulator tumor cells. However, the production of TGF-β by MOPC-315 tumors decreased drastically as a consequence of the low-dose chemotherapy. Thus, the curative effectiveness of low-dosel-PAM therapy for MOPC-315 tumor-bearing mice may be due, at least in part, to a reduction in TGF-β production that enables the development of tumor-eradicating immunity.